Breast carcinoma Research Papers - Academia.edu (original) (raw)

Mena, an actin regulatory protein, functions at the convergence of motility pathways that drive breast cancer cell invasion and migration in vivo. The tumor microenvironment spontaneously induces both increased expression of the Mena INV and decreased expression of Mena11a isoforms in invasive and migratory tumor cells. Tumor cells with this Mena expression pattern participate with macrophages in migration and intravasation in mouse mammary tumors in vivo. Consistent with these findings, anatomical sites containing tumor cells with high levels of Mena expression associated with perivascular macrophages were identified in human invasive ductal breast carcinomas and called TMEM. The number of TMEM sites positively correlated with the development of distant metastasis in humans. Here we demonstrate that mouse mammary tumors generated from EGFP-Mena INV expressing tumor cells are significantly less cohesive and have discontinuous cell-cell contacts compared to Mena11a xenografts. Using the mouse PyMT model we show that metastatic mammary tumors express 8.7 fold more total Mena and 7.5 fold more Mena INV mRNA than early non-metastatic ones. Furthermore, Mena INV expression in fine needle aspiration biopsy (FNA) samples of human invasive ductal carcinomas correlate with TMEM score while Mena11a does not. These results suggest that Mena INV is the isoform associated with breast cancer cell discohesion, invasion and intravasation in mice and in humans. They also imply that Mena INV expression and TMEM score measure related aspects of a common tumor cell dissemination mechanism and provide new insight into metastatic risk.

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- Cell Adhesion, Tumor microenvironment, Mice, Protein Function

Angiogenesis is essential for tumor growth and metastases. Studies in breast carcinomas suggest that microvessel quantitation as a measure of angiogenesis might be one of the most powerful prognostic tools available. Node negative breast cancer is a particular group for which better prognostic markers would be helpful. We therefore measured microvessel density in a series of well characterised node negative breast carcinomas to evaluate angiogenesis as a prognostic marker and assess its relationship to epidermal growth factor receptor (EGFR) and estrogen receptor (ER), which have previously been reported to be of value. 109 patients with a mean age of 55 years and a median follow-up of 25 months were examined. Vessels were immunohistochemically highlighted using an antibody to platelet endothelial cell adhesion molecule CD31, and microvessel density was quantified using a Chalkley point eyepiece graticule. No significant correlation was observed with patient age, tumor size, grade, ER, or EGFR expression. In a univariate analysis of survival, whereas ER expression was not a significant indicator of either relapse-free (RFS) or overall survival (OS), vascular count (VC) predicted both early RFS and OS (p=0.01 and p=0.028 respectively). Furthermore, in patients with ER positive tumors, a subgroup usually considered to have a good prognosis, there was a significant reduction in RFS and OS if tumors had high VCs (p=0.05 and p=0.002 respectively). A further statistically significant reduction in RFS (p=0.05) was observed for EGFR positive highly vascular tumors. In a Cox proportional hazard model, VC remained a significant prognostic indicator for both RFS and OS (p=0.04 and p=0.01) and conferred a 6.6 and 3.5 times respective increased risk of mortality and relapse. These findings suggest that quantitation of angiogenesis is an independent predictor of survival in node negative breast carcinomas, and due to these high hazard ratios might be more useful than other recently described prognostic markers in selecting patients who would benefit from adjuvant therapy.

- by Russell Leek
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- Breast Cancer, Microcirculation, Survival Analysis, Immunohistochemistry

Exposure of human tumor cell lines to different chemotherapeutic drugs, ionizing radiation, and differentiating agents induced morphological, enzymatic, and ploidy changes resembling replicative senescence of normal cells. Moderate doses of doxorubicin induced this senescence-like phenotype (SLP) in 11 of 14 tested cell lines derived from different types of human solid tumors, including all of the lines with wild-type p53 and half of p53-mutated cell lines. SLP induction seemed to be independent from mitotic cell death, the other major effect of drug treatment. Among cells that survived drug exposure, SLP markers distinguished those cells that became terminally growth-arrested within a small number of cell divisions from the cells that recovered and resumed proliferation. SLP induction in breast carcinoma cells treated with retinoids in vitro or in vivo was found to correlate with permanent growth inhibition under the conditions of minimal cytotoxicity, suggesting that this response may be particularly important for the antiproliferative effect of differentiating agents. The senescence-like program of terminal proliferation arrest may provide an important determinant of treatment outcome and a target for augmentation in cancer therapy.

- by Igor Roninson
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- Cancer, Biology, Gamma Rays, Medicine

Background and purpose: Investigation of the use of TomoTherapy and TomoDirect versus conventional radiotherapy for the treatment of post-operative breast carcinoma. This study concentrates on the evaluation of the planning protocol for the TomoTherapy and TomoDirect TPS, dose verification and the implementation of in vivo dosimetry. Materials and methods: Eight patients with different breast cancer indications (left/right tumor, axillary nodes involvement (N+)/no nodes (N0), tumorectomy/mastectomy) were enrolled. TomoTherapy, Tomo-Direct and conventional plans were generated for prone and supine positions leading to six or seven plans per patient. Dose prescription was 42 Gy in 15 fractions over 3 weeks. Dose verification of a TomoTherapy plan is performed using TLDs and EDR2 film inside a home-made wax breast phantom fixed on a randoalderson phantom. In vivo dosimetry was performed with TLDs. Results: It is possible to create clinically acceptable plans with TomoTherapy and TomoDirect. TLD calibration protocol with a water equivalent phantom is accurate. TLD verification with the phantom shows measured over calculated ratios within 2.2% (PTV). An overresponse of the TLDs was observed in the low dose regions (<0.1 Gy). The film measurements show good agreement for high and low dose regions inside the phantom. A sharp gradient can be created to the thoracic wall. In vivo dosimetry with TLDs was clinically feasible. Conclusions: The TomoTherapy and TomoDirect modalities can deliver dose distributions which the radiotherapist judges to be equal to or better than conventional treatment of breast carcinoma according to the organ to be protected.

- by Nadine Linthout
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- Breast Cancer, TomoTherapy, Treatment Outcome, Risk assessment

Current antiestrogen therapy for breast cancer is limited by the mixed estrogenic and antiestrogenic activity of selective estrogen receptor modulators. Here we show that the function of zinc fingers in the estrogen receptor DNA-binding domain (DBD) is susceptible to chemical inhibition by electrophilic disulfide benzamide and benzisothiazolone derivatives, which selectively block binding of the estrogen receptor to its responsive element and subsequent transcription. These compounds also significantly inhibit estrogen-stimulated cell proliferation, markedly reduce tumor mass in nude mice bearing human MCF-7 breast cancer xenografts, and interfere with cell-cycle and apoptosis regulatory gene expression. Functional assays and computational analysis support a molecular mechanism whereby electrophilic agents preferentially disrupt the vulnerable C-terminal zinc finger, thus suppressing estrogen receptor-mediated breast carcinoma progression. Our results provide the proof of principle for a new strategy to inhibit breast cancer at the level of DNA binding, rather than the classical antagonism of estrogen binding.

- by Lihua Wang
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- Breast Cancer, Cell Cycle, Apoptosis, Gene expression
- by Elena Rivera
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- Chemistry, Inflammation, Medicine, Histamine

Purpose: To describe and quantitate the radiological (mammographic and ultrasonographic) characteristics of male breast disease and to report the clinical and pathological findings. Materials and methods: Two-hundred-thirty-six male... more

- by Halil Bozkaya
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- Breast Cancer, Image Analysis, Adolescent, Biopsy

Background: Carcinoma breast is the most common malignancy occurring in females worldwide while in India it is the 2 nd most common malignancy occurring after cervical cancer in females. The incidence is three times higher in urban areas than in rural setup. The disease pattern, clinical and histopathological presentation differs from that of the western world. Methods: The present study was carried out in the Department of Pathology, G.S.V.M. Medical College Kanpur, India from July 2016 to August 2018. Total 54 female were considered for the study, selected on the basis of inclusion and exclusion criteria. Histomorphology and lymph node status in breast carcinomas, the status of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2/neu) in all these breast carcinomas and its prognostic importance in postoperative patient. Results: Present study comprised of total of 54 female patients. Out of all 48.15% cases were found to be in 5 th decade (premenopausal predilection) of life in our setup. The most common type found in the study was Ductal carcinoma (not otherwise specified) seen in 92.6% cases. Lymph node metastasis was found in 66% positive cases. Maximum 54% of cases were histologically classified as grade II. A positive correlation was found between histology and immunohistochemistry. Conclusion: From the present study, it can be concluded that there is a positive correlation between histopathological grade and other prognostic factors including immunohistochemical markers. Immunohistochemical markers can be effectively used to predict prognosis and therapeutic management of patients with carcinoma breast.

Papillary carcinoma of the breast represents approximately 0.5% of all newly diagnosed cases of breast cancer. The prevalence of both invasive and in situ papillary carcinoma seems to be greater older postmenopausal women, and -in relative terms-in males. Histologic features of the tumor include cellular proliferations surrounding fibrovascular cores, with or without invasion. In this review, characteristics of both in situ and invasive disease are outlined. Immunohistochemical analyses of papillary carcinoma suggest the utility of markers such as smooth muscle myosin heavy chain, calponin, p63 and high molecular weight keratins, which can characterize the myoepithelial cell layer. With respect to radiographic evaluation of papillary carcinoma, ultrasonography is the most extensively studied imaging modality, though magnetic resonance mammography has potential utility. Available data suggest improved outcome for papillary carcinoma as compared to invasive ductal carcinoma. Treatment-related information for patients with papillary carcinoma is limited, and patterns noted in available series suggest a variable approach to this disease. The scarcity of information underscores the need for further treatmentand outcome-related studies in papillary carcinoma of the breast.

- by Laura Kruper and +1
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- Cancer, Breast Cancer, Postmenopausal Women, Breast Cancer Early Detecion and Treatment

Incorporating various new and conventional risk factors, the 2005 St Gallen risk categorization is a potentially useful prognostic tool for breast cancers. We conducted a retrospective study to evaluate its application in Hong Kong. Of the 902 included female breast cancers with median follow-up of 5.4 years, 7%, 63% and 30% patients were classified as low-, intermediate-and high-risk categories, respectively. Their corresponding 5-year distant disease-free survivals (DDFS) were 100%, 92% and 72%, respectively (po0.00005). In the intermediate-risk category, node-positive patients had marginally inferior 5-year DDFS than node-negative patients (89% vs. 93%, p ¼ 0.0551). In the high-risk category, patients having HER2 overexpressed tumors and 1-3 positive nodes had significantly better DDFS than other patients with X4 positive nodes (89% vs. 65%, p ¼ 0.0001). Overall, the 2005 St Gallen risk categorization had high prognostic value. However, the impact of HER2 overexpression might be affected by reproducibility of HER2 tests. r

- by Henry Sze
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- Breast Cancer, Treatment Outcome, Risk assessment, Hong Kong

Reduction mammaplasty is one of the most common procedures performed by plastic surgeons all around the world. This procedure is performed for aesthetic or reconstructive purposes, but also offers the opportunity to examine all resected breast tissue histopathologically. The purpose of this study was to evaluate the histologic diagnoses of the reduction mammaplasty specimens retrospectively and to determine the incidence of breast lesions in otherwise asymptomatic and healthy women. Therefore, 149 patients who had undergone reduction mammaplasty were reviewed with regard to their histologic diagnoses. We found that 61% of these women have pathologic alterations in at least one of their breasts, so each patient who requests a breast reduction surgery should be evaluated carefully and the specimens should be handled with particular care.

- by Osman Latifoglu
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- Adolescent, Biopsy, Breast, Clinical Sciences

HER2/neu gene amplification is being evaluated by fluorescent in situ hybridization (FISH). In order to avoid interobserver variations in the assessment of HER2/neu status, an integrated FISH image analysis system is developed to automate the classification of FISH images from breast carcinomas. Using a two-stage algorithm, for nuclei and dot detection, and combining results from multiple images taken from a slice for overall case classification, FISH signals ratio per cell nucleus were measured and cases were classified as positive or negative. The system consists of functions for red spot detection, green spot detection, nuclei segmentation and FISH signal ratio. Therefore, it provides the capability to manually correct the resulted images after the analysis.

- by F. Raimondo
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- Breast Cancer, Image Analysis, Medicine, Fluorescent in situ hybridization

Oncocytic tumors are a distinctive class of proliferative lesions composed of cells with a striking degree of mitochondrial hyperplasia that are particularly frequent in the thyroid gland. To understand whether specific mitochondrial DNA (mtDNA) mutations are associated with the accumulation of mitochondria, we sequenced the entire mtDNA in 50 oncocytic lesions (45 thyroid tumors of epithelial cell derivation and 5 mitochondrion-rich breast tumors) and 52 control cases (21 nononcocytic thyroid tumors, 15 breast carcinomas, and 16 gliomas) by using recently developed technology that allows specific and reliable amplification of the whole mtDNA with quick mutation scanning. Thirteen oncocytic lesions (26%) presented disruptive mutations (nonsense or frameshift), whereas only two samples (3.8%) presented such mutations in the nononcocytic control group. In one case with multiple thyroid nodules analyzed separately, a disruptive mutation was found in the only nodule with oncocytic features. In one of the five mitochondrion-rich breast tumors, a disruptive mutation was identified. All disruptive mutations were found in complex I subunit genes, and the association between these mutations and the oncocytic phenotype was statistically significant (P ‫؍‬ 0.001). To study the pathogenicity of these mitochondrial mutations, primary cultures from oncocytic tumors and corresponding normal tissues were established. Electron microscopy and biochemical and molecular analyses showed that primary cultures derived from tumors bearing disruptive mutations failed to maintain the mutations and the oncocytic phenotype. We conclude that disruptive mutations in complex I subunits are markers of thyroid oncocytic tumors.

- by Christine Betts
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- Electron Microscopy, Multidisciplinary, Mitochondrial DNA, Mutation

Weight gain is a reported problem associated with adjuvant chemotherapy for breast cancer and often generates psychosocial stress in women [1]. It also may affect prognosis and survival. Changes in body composition and weight during chemotherapy, particularly adjuvant treatment of breast carcinoma, have been previously reported [1-3]. Multiple reasons for this weight gain have been suggested though few theories have been scientifically validated [4]. The aim of this study was to investigate body composition and its relationship to weight change associated with the CMF-based breast cancer chemotherapy protocols. Total body nitrogen (TBN), body fat, total body water (TBW), and anthropometric measurements were conducted on 25 female out-patients (median age 47, range 26-70 years) receiving adjuvant CMF-based chemotherapy for breast cancer. Total body nitrogen was measured using the In Vivo Neutron Capture Analysis (IVNCA) technique (on day 1 of cycles 2-6) and TBP was calculated by multiplying TBN by 6.25 [5]. Nitrogen Index (NI) was calculated by expressing TBN as a percentage of normal. There was a significant increase in mean body weight during chemotherapy of 2.35 kg (p < 0.0001). Serial measurements showed no significant change in mean TBN, NI, or percentage body fat. Break down of body weight showed a significant increase in mean TBW of 0.79 kg (p = 0.003) and mean fat mass of 1.49 kg (p = 0.008). We conclude that weight gain observed during adjuvant chemotherapy for breast carcinoma is primarily due to an increase in fat and TBW.

Signal transducers and activators of transcription (STATs) were originally identified as key components of signaling pathways involved in mediating responses to IFNs. Previous studies showed that the Src oncoprotein constitutively activates one STAT family member, Stat3. In this study, we investigated STAT activation in a panel of rodent fibroblast cell lines stably transformed by diverse viral oncoproteins. Using a temperature-sensitive

- by Thomas Smithgall
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- Signal Transduction, Cell line, Mice, T cells

The objective of this article is to introduce the early Chinese clinical experience of using extracorporeal focused ultrasound (US) surgery (FUS) for the treatment of solid tumors. From December 1997 to October 2001, a total of 1038 patients with solid tumors underwent FUS ablation in 10 Chinese hospitals. The tumors included primary and metastatic liver cancer, malignant bone tumors, breast cancer, soft tissue sarcomas, kidney cancer, pancreatic cancer, abdominal and pelvic malignant tumors, uterine myoma, benign breast tumors, hepatic hemangioma and other solid tumors. In this article, pathologic changes in tumors treated with FUS, real-time diagnostic imaging for targeting, monitoring and assessment of results by follow-up images are presented. Early clinical results and complications of the technique are also reported. (E-mail: mfengwu@yahoo.com) © 2004 World Federation for Ultrasound in Medicine & Biology.

- by Hui zhu
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- Magnetic Resonance Imaging, Breast Cancer, Treatment Outcome, Pancreatic Cancer

Phantom breast syndrome (PBS) represents the experience of the continued presence of the breast, after mastectomy. Our aim was to assess PBS appearance by means of a structured questionnaire and to look into possible associations to disease and treatment parameters, in 105 women with breast cancer treated by mastectomy. PBS was recorded in 22.9% of the patients. In the majority of cases phantom experience had the size (88.9%), shape (76.5%) and weight (64.7%) of the normal breast and was localised in the entire breast (50%). Concerning disease parameters, no association with primary tumour size (T) or lymph node status was detected, but interestingly, in situ breast cancer (DCIS) was found to be more frequently associated with PBS, compared with invasive tumours. No significant associations of PBS with previous sensory experiences of the breast, radiotherapy or systemic treatment were assessed. The results are interpreted within the frame of Melzack's theory of a neuromatrix, as...

- by Iannis Zervas
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- Psychiatry, Nonparametric Statistics, Breast Cancer, Mastectomy

Salivary duct car~ ittoma (SDC) it a recently de~crlbed highly malignant tumor, seet~[ mo~t commoMv in the parot~d gland & occar~ in the 6 'h and 7 ~' decade o[ hfe. Rarely, it occur~ il~] the minor ~'alivary gland~. 7he ea~e ts presented because oJ tt~ rare occurrence and unttsl~ally I pre~etttit~g as a ~welling predominantly invohutg the maxillary bone. The tumor bear~ hi~'tologicaq homology with breast car~ tnoma, prostattc carcinoma and ~weat duct carcinoma. I Keu Words : minor sahvary duct carcinoma, comedo pattern.

- by Bharat Rekhi
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- Indian, Breast carcinoma, Parotid Gland, Salivary Gland

Literature data suggest that breast cancers occurring in young patients may be different from those arising in older women. In this study the clinicopathologic characteristics of 50 patients under 40 years of age were compared with those of patients aged over 60. Patients under 40 years old more frequently had a family history of breast cancer than did older patients (24% vs 17%) and had more often used oral contraceptives (29% vs 13%); on average they had experienced menarche 1 year earlier. For early onset breast carcinomas there was a higher frequency of grade 3 tumours (38% vs 17%) and oestrogen receptor negativity (46% vs 20%). In addition, in younger patients the carcinomas were mostly DNA aneuploid (78% vs 58%), with a higher proliferation rate (48% vs 26%) and more frequent c-erbB-2 overexpression (48% vs 26%) and p53 alteration (30% vs 8%). Our data demonstrate that breast cancers arising in young women have a significantly different biopathological profile from those in older patients, with a predominance of unfavourable prognostic parameters.

- by Antonio Cavaliere
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- Breast Cancer, Risk assessment, Family history, Probability

Invasive breast cancer is a heterogeneous disease in its presentation, pathological classification and clinical course. However, there are more than a dozen variants which are less common but still very well defined by the World Health Organization (WHO) classification. The rarity of many of these neoplasms does not allow large or randomized studies to define the optimal treatment. Many of the descriptions of these cancers are from case reports and small series. Our review brings updated information on 16 epithelial subtypes as classified by the WHO system with a very concise histopathology description and parameters helpful in the clinic. The aim of our review is to provide a tool for breast cancer caregivers which will enable a better understanding of the disease and its optimal approach to therapy. This may also stand as a clinical framework for a future understanding of these rarer breast cancers when gene analysis work is reported.

- by Rinat Yerushalmi
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- Breast Cancer, Case Report, Breast carcinoma, Prognosis

Adjuvant radiotherapy to the breast plays a significant role in preventing local failure in women treated for early stage breast cancer. This fact is supported by multiple clinical trials demonstrating that adjuvant radiotherapy decreases the risk of local recurrence and increases the rate of breast preservation, and actually the rules of adjuvant breast irradiation are clearly established. Sarcomas are a

- by Bernard Asselain
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- Clinical Trial, Breast Cancer, Radiation Therapy, Treatment Outcome

Background: Arrest of the cell cycle in G2 phase following DNA damage helps protect cell viability by allowing time for DNA repair before entry into mitosis (M phase). Abrogation of G 2 arrest sensitizes cells to the effects of DNA-damaging agents. UCN-01 (7-hydroxystaurosporine), a protein kinase C inhibitor that may block G 2 checkpoint regulation, has been reported to enhance the cytotoxicity of mitomycin C, a known DNA-damaging agent. Purpose: We studied the effect of UCN-01 on G 2 checkpoint control in human lymphoma CA46 cells, whose sensitivity to various DNA-damaging agents and G2 response to DNA damage have been characterized. We also assessed the ability of UCN-01 to enhance the cytotoxicity of y irradiation in CA46 cells and human colon carcinoma HT-29 cells, both of which are mutant for p53 function. The influence of p53 function on UCN-01mediated abrogation of the G 2 checkpoint and enhancement of DNA-damaging agent cytotoxicity was studied in transfected human breast carcinoma MCF-7 cells that either expressed or did not express the human papillomavirus type-16 E6 protein. MCF-7 cells have normal p53 function, and the E6 protein binds p53 protein and promotes its destruction. Methods: The effect of UCN-01 on cell cycle arrest induced by y irradiation was studied in CA46 cells and in transfected MCF-7 cells by use of flow cytometry. A histone HI phosphorylation assay was employed to measure cyclin Bl/Cdc2 kinase activity in extracts derived from irradiated and nonirradiated CA46 cells that had been either treated or not treated with UCN-01; the phosphorylation status of Cdc2 kinase protein in the same extracts was determined by use of western blotting. The effect of UCN-01 on the cytotoxicity of y irradiation in CA46 and HT-29 cells was determined by use of MTT (thiazolyl blue) and clonogenic (colony-forming) assays, respectively; a clonogenic assay was also used to measure the effect of UCN-01 on the cytotoxicity of cisplatin in transfected and nontransfected MCF-7 cells.

- by Edward Sausville and +1
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- Flow Cytometry, Cell Cycle, Gamma Rays, DNA damage

Objective To assess clinical variables that may be useful in differentiating gynaecomastia from carcinoma and to analyse the contribution of mammography and ultrasound to the evaluation of male breast disease. Methods All men who underwent mammography and/or ultrasound between 1993 and 2006 in our hospital were retrospectively evaluated. Clinical characteristics in patients with gynaecomastia and those with carcinoma were compared. Radiological findings were classified according to the BI-RADS (Breast Imaging Reporting and Data System) criteria. The diagnostic performance of physical examination, mammography and ultrasound was determined and compared. Results A total of 628 patients with 518 mammograms and 423 ultrasounds were reviewed. The final diagnoses were: 19 carcinomas, 526 gynaecomastias, 84 other benign conditions and 25 normal. There were statistically significant differences in age, bilateral involvement, clinical presentation and physical examination between patients with carcinoma and those with gynaecomastia. The diagnostic performance of physical examination was lower than that of mammography and ultrasound (p<0.05 for specificity). Mammography was the most sensitive (94.7%) and ultrasound the most specific (95.3%) for detection of malignancy (p>0.05). We propose an algorithm for the use of mammography and ultrasound in men. Conclusions Mammography and ultrasound, with a negative predictive value close to 100%, make it possible to avoid very many unnecessary surgical procedures in men.

- by Jose Povedano
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- Ultrasound, Spain, Breast Imaging, Statistical Significance

La reconstrucción mamaria posmastectomía, se considera actualmente parte integral del tratamiento multidisciplinario del carcinoma de mama, pues contribuye a restaurar de una forma objetiva, la imagen corporal de la paciente y revierte las secuelas psicológicas negativas, ocasionadas por la mastectomía. Las técnicas reconstructivas de la mama consisten en la aplicación de una serie de técnicas quirúrgicas con posibilidades de aplicación selectiva o adyuvantes, en función de las necesidades y posibilidades de la paciente. En este trabajo se destaca las modalidades de intervención del fisioterapeuta, en las distintas etapas del proceso quirúrgico, como miembro del equipo multidisciplinar de la Asociación de Mujeres Andaluzas Mastectomizadas (AMAMA). Así mismo, se establece

- by Itzam Martínez
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- Breast Cancer, Quality of life, Physical Therapy, Reconstruction
- by Anne Tardivon
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- Breast carcinoma

Sodium iodide symporter (NIS) is a molecule involved in active accumulation of iodine in thyroid gland for the biosynthesis of thyroid hormone. Its expression has also been demonstrated in extra-thyroidal tissues including lactating mice mammary gland and also in human breast cancers. Iodide transport in thyroid cells through NIS is the basis for using radioiodine for diagnosis and treatment of differentiated thyroid carcinoma. The similar approach may prove beneficial for the diagnosis and treatment of breast cancer if iodine uptake, its retention and NIS expression can be shown unequivocally in malignant tumors. The aim of the present study was to investigate NIS expression, in vivo iodine transport ability and fate of iodine in human breast tumors. Women (age 33-58 years) with infiltrating duct carcinoma confirmed by FNAC and subsequent histopathology were the subject of this study. Expression of NIS RNA and protein was confirmed by RNAase protection assay, western blot and immunohistochemistry respectively in surgically excised breast tumor tissue. Iodine transport ability and its nature was assessed both in vivo and in vitro. We report high NIS expression at both transcriptional and translational level and its ability to transport iodine in human breast tumors. The in vivo iodine transport ability was confirmed by scintigraphy. Unlike thyroid, perchlorate and thiocyanate do not inhibit iodine transport in breast tumors. The presence of iodinated proteins suggests the longer retention time. The unequivocal demonstration of NIS expression, its functionality and retention of iodine by organification further provides supportive evidence for use of radioiodine as an additional treatment modality of human breast carcinoma.

- by Madan Godbole
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- Pathology, Molecular Biology, RNA, Breast Cancer
- by Ulrich Pfeffer
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- Cancer, Breast Cancer, Immunohistochemistry, Endothelial Cells

Hereditary breast cancer accounts for up to 5-10% of all breast carcinomas. Recent studies have demonstrated that mutations in two high-penetrance genes, namely BRCA1 and BRCA2, are responsible for about 16% of the familial risk of breast cancer. Even though subsequent studies have failed to find another high-penetrance breast cancer susceptibility gene, several genes that confer a moderate to low risk of breast cancer development have been identified; moreover, hereditary breast cancer can be part of multiple cancer syndromes. In this review we will focus on the hereditary breast carcinomas caused by mutations in BRCA1, BRCA2, Fanconi anaemia (FANC) genes, CHK2 and ATM tumour suppressor genes. We describe the hallmark histological features of these carcinomas compared with non-hereditary breast cancers and show how an accurate histopathological diagnosis may help improve the identification of patients to be screened for mutations. Finally, novel therapeutic approaches to treat patients with BRCA1 and BRCA2 germ line mutations, including cross-linking agents and PARP inhibitors, are discussed.

- by David Tan
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- Molecular Biology, Breast Cancer, Molecular Genetics, DNA repair

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- by Emmanuelle Mouret-fourme
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- Breast Cancer, Clinical Sciences, Breast carcinoma

The estrogen receptor-a (ER) plays a crucial role in normal breast development and is also linked to development and progression of mammary carcinoma. The transcriptional repression of ER-a gene in breast cancer is an area of active investigation with potential clinical significance. However, the molecular mechanisms that regulate the ER-a gene expression are not fully understood. Here we show a new molecular mechanism of ER-a gene inactivation mediated by pRb2/p130 in ER-negative breast cancer cells. We investigated in vivo occupancy of ER-a promoter by pRb2/p130-E2F4/5-HDAC1-SUV39 H1-p300 and pRb2/p130-E2F4/5-HDAC1-SUV39H1-DNMT1 complexes, and provided a link between pRb2/ p130 and chromatin-modifying enzymes in the regulation of ER-a transcription in a physiological setting. These findings suggest that pRb2/p130-multimolecular complexes can be key elements in the regulation of ER-a gene expression and may be viewed as promising targets for the development of novel therapeutic strategies in the treatment of breast cancer, especially for those tumors that are ER negative.

- by Giuseppe Russo
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- Breast Cancer, Transcription Factors, Gene expression, Molecular Mechanics

The gene coding foi human collagenase-3 (CLG3), a recently described matrix metalloproteinase produced by breast carcinomas, has been localized by fluorescence in situ hybridization on chromosome llq22.3. Physical mapping of an isolated YAC clone containing CLG3 has revealed that this gene is tightly linked to those encoding other matrix metalloproteinases, including fibroblast collagenase (CLGl), stromelysin-1 (STMYl), and stromelysin-2 (STMY2). Further mapping of this region using pulsed-field gel electrophoresis has shown that the CLG3 gene is localized to the telomeric side of the matrix metalloproteinase cluster, the relative order of the loci being centromere -STMY2 -CLGl -STMYl -CLG3 -telomere.

- by Alberto M Pendas
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- Information Systems, Genetics, Genomics, Fluorescent in situ hybridization

Reçu le 19 novembre 2002 ; reçu en forme révisée le 17 mars 2003 ; accepté le 19 mars 2003 Résumé Objectifs. -Le cancer du sein survenant chez la femme très jeune est rare et son diagnostic et sa prise en charge sont parfois difficiles. L'objectif de l'étude était d'en analyser les caractéristiques épidémiologiques et clinicopathologiques et surtout d'évaluer les résultats des thérapeutiques instaurées. Patientes et méthodes. -Les dossiers de trente patientes âgées de 30 ans ou moins, chez qui un diagnostic de cancer invasif du sein a été porté entre 1986 et 2001, ont fait l'objet d'une étude rétrospective dans le service de radiothérapie du centre Alexis-Vautrin. Résultats. -Six patientes (20 %) avaient un antécédent familial de cancer mammaire. Dans 90 % des cas, le signe révélateur était un nodule cliniquement palpable, de taille moyenne de 3,5 cm. Il s'agissait de 11 cancers de stade I, 11 de stade II, de 6 de stade III et de deux de stade IV. Cinq cancers ont été découverts au décours d'une grossesse (taille clinique moyenne = 5,8 cm). Une chimiothérapie néoadjuvante a été prescrite chez 11 patientes. Vingt trois fois sur 28 (82 %), le sein a pu être conservé. Il s'agissait d'un carcinome canalaire infiltrant de grade III dans 13/27 cas et une fois sur deux, il s'accompagnait d'une atteinte ganglionnaire axillaire. Les récepteurs oestrogéniques étaient absents dans 11/26 cas. Après un suivi post-thérapeutique médian de 5 ans, on a constaté six récidives locales (20 %), quatre cancers du sein controlatéral et trois cancers secondaires. Dix patientes (38 %) sont décédées dans un tableau d'évolution métastatique ultérieure. Le taux de survie globale à 5 ans était de 78 %. Conclusion. -Ces résultats rejoignent les données de la littérature qui soulignent le pronostic défavorable du cancer du sein chez les femmes très jeune et incitent à adapter en fonction de l'ensemble des facteurs pronostiques les indications des thérapeutiques locales et des traitements adjuvants systémiques et hormonaux. © 2003 Éditions scientifiques et médicales Elsevier SAS. Tous droits réservés.

- by Christian Marchal
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- Breast Cancer, Family history, Young Women, Breast carcinoma

There is compelling evidence from transgenic mouse studies and analysis of mutations in human carcinomas indicating that the TGF-β signal transduction pathway is tumor suppressive. We have shown that overexpression of TGF-β1 in mammary epithelial cells suppresses the development of carcinomas and that expression of a dominant negative type II TGF-β receptor (DNIIR) in mammary epithelial cells under control of the MMTV promoter/enhancer increases the incidence of mammary carcinomas. Studies of human tumors have demonstrated inactivating mutations in human tumors of genes encoding proteins involved in TGF-β signal transduction, including DPC4/Smad4, Smad2, and the type II TGF-β receptor (TβRII). There is also evidence that TGF-β can enhance the progression of tumors. This hypothesis is being tested in genetically modified mice. To attain complete loss of TβRII, we have generated mice with loxP sites flanking exon 2 of Tgfbr2 and crossed them with mice expressing Cre recombinase under control of the MMTV promoter/enhancer to obtain Tgfbr2 mgKO mice. These mice show lobuloalveolar hyperplasia. Mice are being followed for mammary tumor development. Tgfbr2 mgKO mice that also express polyoma virus middle T antigen under control of the MMTV promoter (MMTV-PyVmT) develop mammary tumors with a significantly shorter latency than MMTV-PyVmT mice and show a marked increase in pulmonary metastases. Our data do not support the hypothesis that TGF-β signaling in mammary carcinoma cells is important for invasion and metastasis, at least in this model system. The importance of stromal-epithelial interactions in mammary gland development and tumorigenesis is well established. These interactions probably involve autocrine and paracrine action of multiple growth factors, including members of the TGF-β family, which are expressed in both stroma and epithelium. Again, to accomplish complete knockout of the type II TGF-β receptor gene in mammary stromal cells, FSP1-Cre and Tgfbr2 flox/flox mice were crossed to attain Tgfbr2 fspKO mice. The Despite over a decade of scrutiny and over 20 published reports from various countries, the degree to which ATM mutations lead to breast References 1. Gatti RA, Tward A, Concannon P: Cancer risk in ATM heterozygotes: a model of phenotypic and mechanistic differences between missense and truncating mutations. Mol Biol Metab 1999, 68:419-423. 2. Spring K, Ahangari F, Scott SP, Waring P, Purdie DM, Chen PC, Hourigan K, et al.: Mice heterozygous for mutation in Atm, the gene involved in ataxia-telangiectasia, have heightened susceptibility to cancer. Nat Genet 2002, 32:185-190. 3. Scott SP, Bendix R, Chen P, Clark R, Dork T, Lavin MF: Missense mutations but not allelic variants alter the function of ATM by dominant interference in patients with breast cancer. Proc Natl Acad Sci USA 2002, 99:925-930. 4. Concannon P: ATM heterozygosity and cancer risk. Nat Genet 2002, 32:89-90. 5. Chenevix-Trench G, Spurdle AB, Gatei M, Kelly H, Marsh A, Chen X, Donn K, et al.: Dominant negative ATM mutations in breast cancer families.

- by Elda Tagliabue
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- Breast Cancer, Extracellular Matrix, Breast carcinoma

With the advent of personalized medicine, anatomic pathology-based molecular assays, including in situ hybridization (ISH) and mRNA detection tests, are performed routinely in many laboratories and have increased in their clinical importance and complexity. These assays require appropriately fixed tissue samples that preserve both nucleic acid targets and histomorphology to ensure reliable test results for determining patient treatment options. However, all aspects of tissue processing, including time until tissue fixation, type of fixative, duration of fixation, post-fixation treatments, and sectioning of the sample, impact the staining results. ASCO/CAP has issued pre-analytical guidelines to standardize tissue processing for HER2 testing in breast carcinoma specimens: 10% neutral-buffered formalin (NBF) with a fixation time from at least 6 to 48 h [1]. Often, this recommendation is not followed to the detriment of staining results .

- by Abigail McElhinny and +3
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- Personalized Medicine, In Situ Hybridization, Methods, Cell line

In women who develop bone metastases from breast cancer (BC), interactions between tumor cells and osteoclasts within the bone lead to localized bone destruction and increase the risk of skeletal-related events (SREs). Bisphosphonates inhibit osteoclast-mediated bone resorption, and have been used extensively for treating post-menopausal osteoporosis and reducing the risk of SREs in patients with bone metastases. A number of clinical trials in women with early stage BC have demonstrated that adding bisphosphonates to adjuvant endocrine therapy can prevent bone loss and may prevent disease recurrence and improve disease-free survival. In women with bone metastases from BC, bisphosphonates have demonstrated efficacy for reducing skeletal morbidity and pain and improving quality of life. Recent economic analyses have demonstrated that bisphosphonate therapy is a cost-effective use of healthcare resources. This review summarizes the available data for bisphosphonate benefits in both the adjuvant and metastatic settings in the context of evolving clinical practice.

- by Louise Provencher
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- Cancer, Risk factors, Carcinoma, Breast carcinoma

La enfermedad de Paget mamaria (EP) es una manifestación superficial de enfermedad maligna de la mama. Suele presentarse entre 1 y 3% de todos los cánceres de mama y afecta principalmente mujeres entre los 50 y 60 años de edad. La forma clínica clásica se manifiesta con una placa infiltrada unilateral con eritema, escamas y en etapas avanzadas secreción del pezón o retracción del mismo. Presentamos el caso de una paciente de 51 años quién presentó dermatosis localizada a pezón izquierdo constituida por una placa eritemato-escamosa con costras hemáticas, de ocho meses de evolución, con prurito leve. Se le realizó biopsia y se diagnosticó enfermedad de Paget con carcinoma intraductal.

- by Marcia Káram-Orantes
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- Breast carcinoma, Clinical Presentation

Relative to her risk of breast carcinoma, the woman with a BRCA1 or BRCA2 gene mutation can be managed either by intensive screening (with or without chemoprevention) or by prophylactic mastectomy. Although it would be preferable to avoid prophylactic surgery, the current level of screening technology and the rudimentary state of chemoprevention do not guarantee a good outcome with intensive surveillance. A review of the currently available data was undertaken to determine the efficacy of prophylactic surgery, intensive screening, and chemoprevention. An attempt then was made to extrapolate the efficacy of the various approaches to the management of women who carry BRCA1 or BRCA2 gene mutations. Intensive surveillance may not detect breast carcinoma at an early, curable stage in young women with BRCA1 or BRCA2 gene mutations because the growth rate of the tumors in these women most likely will be rapid and the density of the breast tissue may compromise detection. Chemoprevention is in its infancy, and its efficacy in this population is unknown. Conversely, prophylactic surgery may not be completely effective in preventing breast carcinoma. The authors are hopeful that sometime in the next decade advances in chemoprevention, screening technology, or breast carcinoma treatment will make mastectomy obsolete. However, for the time being prophylactic mastectomy has attributes that make it an alternative for this population that must be considered. Careful discussion of all options is essential in the management of these women.

- by moshe papa
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- Cancer, Transcription Factors, Genetic Testing, Mutation

Background The introduction of skin-sparing mastectomy has revolutionized both breast cancer surgery and breast reconstruction. Latissimus dorsi myocutaneous flap is a versatile flap that is gaining renewed popularity with the development of flap modifications and the continued recognition of its reliability and safety. We report our results with a new modification of the extended latissimus dorsi flap after skin-sparing mastectomy for breast cancer. patients of breast carcinoma had unilateral skin-sparing mastectomy and immediate breast reconstruction. A total of 132 cases of invasive duct carcinoma and eight cases of invasive lobular carcinoma are included. Age ranged from 27 to 53 (median, 40.5) years. Tumor stage was stage I in 22 cases, stage II in 100 cases, and stage III in 18 cases. We performed a new modification to the standard extended latissimus dorsi flap, which allowed us to obtain enough autologous tissue to reconstruct the relatively large breast of the Egyptian women without implant. The postoperative aesthetic results and donor side morbidity, including contour deformity and scaring, were examined. Results We applied both an objective and subjective aesthetic result monitoring. Aesthetic grading results of breast reconstruction were excellent in 85, good in 42, fair in ten and poor in three cases. Both flap and donor site complications were minor. Patients were followed for a median of 32.4 (range, 12-48) months. During this period of follow-up, no episode of local or distant failure was observed.

- by Bryant Toth and +1
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- Breast Cancer, Treatment Outcome, Egypt, Patient Satisfaction

Accepté pour publication le 11 octobre 2010 Disponible sur Internet le 26 janvier 2011

Background: Disruption of the balance between apoptosis and proliferation is considered to be an important factor in the development and progression of tumor. In this study we determined the in vivo cell kinetics along the spectrum of apparently normal epithelium, hyperplasia, preinvasive lesions and invasive carcinoma, in breast tissues affected by fibrocystic changes in which preinvasive and/or invasive lesions developed, as a model of breast carcinogenesis. Materials and method: A total of 32 areas of apparently normal epithelium and 135 ductal proliferative and neoplastic lesions were studied. More than one epithelial lesion per case was analyzed. The apoptotic index (AI) and the proliferative index (PI) were expressed as the percentage of TUNEL (TdT-mediated dUTP-nick end-labelling) and Ki-67 positive cells, respectively. The proliferative/apoptotic index (P/A) was calculated for each case. Results: Statistical analysis demonstrated significant differences among the tissue groups for both indices (P < 0.0001). The Als and PIs were significantly higher in hyperplasia than in apparently normal epithelium (P = 0.04 and P = 0.0005, respectively), in atypical hyperplasia than in hyperplasia (P = 0.01 and P = 0.04, respectively) and in invasive carcinoma than in in situ carcinoma (P = 0.0001 and P < 0.0001, respectively). The two indices were similar in atypical hyperplasia and in in situ carcinoma. The P/A index increased significantly from normal epithelium to hyperplasia (P = 0.01) and from preinvasive lesions to invasive carcinoma (P = 0.04), whereas it was decreased (NS) from hyperplasia to preinvasive lesions. A strong positive correlation between the Als and the Pls was found (r = 0.83; P < 0.0001). Conclusion: These findings suggest accelerating cell turnover along the continuum of breast carcinogenesis. Atypical hyperplasias and in situ carcinomas might be kinetically similar lesions. In the transition from normal epithelium to hyperplasia and from preinvasive lesions to invasive carcinoma, the net growth of epithelial cells results from a growth imbalance in favour of proliferation. In the transition from hyperplasia to preinvasive lesions there is an imbalance in favour of apoptosis.

- by John Hilkens
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- Breast Cancer, Breast carcinoma

The receptor tyrosine kinase ERBB2 plays a central role in the development of breast cancer and other epithelial malignancies. Elevated ERBB2 activity is believed to transform cells by transmitting mitogenic and antiapoptotic signals. Here we show that tightly regulated overexpression of oncogenic ERBB2 in human breast carcinoma cells does not stimulate proliferation but provokes premature senescence, accompanied by up-regulation of the cyclin-dependent kinase inhibitor P21 WAF1/CIP1 . A similar effect was caused by retrovirusmediated overexpression of oncogenic ERBB2 in low-passage murine embryonic fibroblasts. In contrast to previous observations based on constitutively overexpressing cell lines, P21 induced by tetracycline-regulated ERBB2 localizes to the nucleus in arrested cells. P21 up-regulation seems to be independent of the P53 tumor suppressor protein, and senescence-associated phenotypic alterations are reversed by specific inhibition of P38 mitogen-activated protein kinases. Functional inactivation of P21 by antisense oligonucleotides is sufficient to prevent cell cycle arrest as well as the senescent phenotype, thereby identifying the P21 protein as the key mediator of hypermitogenic cell cycle arrest and premature senescence in breast carcinoma cells. Our results may thus indicate that premature senescence represents an inherent anticarcinogenic program during ERBB2-driven mammary tumorigenesis. We propose a multistep model for the process of malignant transformation by ERBB2 wherein secondary lesions either target P21 or downstream effectors of senescence to bypass this primary fail-safe mechanism. (Cancer Res 2005; 65(3): 840-9) Note: T.M. Trost and E.U. Lausch contributed equally to this work. Requests for reprints: Christian Spangenberg, Children'

- by lili r
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- Cancer, Breast Cancer, Cell Cycle, Signal Transduction

Carcinoma of the breast, the third most common cancer worldwide, accounts for the highest morbidity and mortality. Oxygen free radicals are able to cause dam- age to membranes, mitochondria and macromolecules including proteins, lipids and DNA. Accumulation of DNA damages has been suggested to contribute to carcinogenesis. In the present study, the relationship between oxidative stress and some enzyme activities in breast cancer was investigated. Malondialdehyde level, catalase, glu- tathione peroxidase, glucose-6-phosphate dehydrogenase, pyruvate kinase and arjinase activities in tumor tissues and adjacent normal tissues of 10 patients with invasive ductal carcinoma were determined. Higher malondialdehyde levels were observed in tumor tissues than noncancerous tissues (p<0.001). The activities of catalase, glutathione peroxidase, glucose-6- phosphate dehydrogenase, pyruvate kinase, arjinase in tumor tissues significantly increased compared to the control (p<0.001). We suggest...

- by Seval Yilmaz
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- Breast Cancer, DNA damage, Peroxidase, Pyruvate Kinase
- by B. Ojeda
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- Breast Cancer, Breast carcinoma

A series of sulfapyridine-polyhydroxyalkylidene (or arylidene)-imino derivatives (Schiff's bases) 2a-c and 4a-e were prepared by condensation of 4-amino-N-pyridin-2-ylbenzenesulfonamide (1) with different monosaccharides or with aromatic aldehydes. Treatment of 2a-c with thioglycolic acid led to the formation of the C-nucleosides (3a-c), while treatment of 4a-e with thioglycolic and/or thiosalicylic acids afforded the corresponding 2-arylthiazolidin-4-one or 2-arylbenzothiazin-4-one derivatives 5a-e and/or 6a-e, respectively. Some representative examples of the newly prepared compounds showed considerable cytotoxic effect against breast carcinoma cell line MCF7 and cervix carcinoma cell line HELA in comparison with 5-flurouracil and doxorubicin. AutoDock molecular docking into PTK has been done for lead optimization of the compounds in study as potential PTK inhibitors.

- by manal anwar
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- Organic Chemistry, Cell line, Protein Tyrosine Kinase, Molecular docking

A role of X chromosome inactivation process in the development of breast cancer have been suggested. In particular, the relationship between the breast cancer predisposing gene BRCA1 and XIST, the main mediator of X chromosome inactivation, has been intensely investigated, but still remains controversial. We investigated this topic by assessing XIST behaviour in different groups of breast carcinomas and in a panel of breast cancer cell lines both BRCA1 mutant and wild type. In addition, we evaluated the occurrence of broader defects of heterochromatin in relation to BRCA1 status in breast cancer cells. We provide evidence that in breast cancer cells BRCA1 is involved in XIST regulation on the active X chromosome, but not in its localization as previously suggested, and that XIST can be unusually expressed by an active X and can decorate it. This indicates that the detection of XIST cloud in cancer cell is not synonymous of the presence of an inactive X chromosome. Moreover, we show that global heterochromatin defects observed in breast tumor cells are independent of BRCA1 status. Our observations sheds light on a possible previously uncharacterized mechanism of breast carcinogenesis mediated by XIST misbehaviour, particularly in BRCA1-related cancers. Moreover, the significant higher levels of XIST-RNA detected in BRCA1-associated respect to sporadic basal-like cancers, opens the possibility to use XIST expression as a marker to discriminate between the two groups of tumors.

- by S. Tabano
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- Breast Cancer, Long Noncoding Rna, Multidisciplinary, RNA interference

Since germline mutations in the PALB2 (Partner and Localizer of BRCA2) gene have been identified as breast cancer (BC) susceptibility alleles, the geographical spread and risks associated with PALB2 mutations are subject of intense investigation. Patients with bilateral breast cancer constitute a valuable group for genetic studies. We have thus scanned the whole coding region of PALB2 in a total of 203 German or Russian bilateral breast cancer patients using an approach based on high-resolution melting analysis and direct sequencing of genomic DNA samples. Truncating PALB2 mutations were identified in 4/203 (2%) breast cancer patients with bilateral disease. The two nonsense mutations, p.E545X and p.Q921X, have not been previously described whereas the two other mutations, p.R414X and c.509_510delGA, are recurrent.

- by Anna Sokolenko
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- Genetics, Breast Cancer, Russia, Germany

We report a case of synchronous bilateral breast cancer in a patient with ambiguous external genitalia attributed to a 45,X/46,XY mosaicism. To our knowledge, this represents the first such case ever to be reported. Mammography, ultrasonography, computed tomography, and magnetic resonance imaging all showed bilateral suspicious breast masses with microcalcifications. There were no radiological findings of muscle invasion or axillary lymphadenopathy. The patient was successfully treated by bilateral radical modified mastectomy followed by external irradiation and adjuvant endocrine therapy. Histological examination revealed a bilateral ductal carcinoma in situ, with a cribriform and papillary pattern and microfoci of infiltrating ductal carcinoma. The hormonal profile revealed high levels of follicle-stimulating hormone and luteinizing hormone, and low levels of testosterone. Testicular sonography revealed small hypoechoic testicles with bilateral microlithiasis. This case shows that 45,X/46,XY men may have an increased risk of breast cancer and must be followed up carefully.

- by Claudio Coco
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- Computed Tomography, Breast Cancer, Ductal carcinoma in situ, Ultrasonography