Co-expression of p16, Ki67 and COX-2 is associated with basal phenotype in high-grade ductal carcinoma in situ of the breast (original) (raw)
Related papers
Bratislava Medical Journal, 2014
Background: Recent studies have showed a signifi cant association between the combination of COX-2, p16 and Ki67 overexpression and incidence of subsequent invasive carcinoma in a subgroup of treated ductal carcinoma in situ (DCIS) and the indicated prognostic value of COX-2, p16 and Ki67 in early breast cancer. Based on the continual model of carcinogenesis and the mentioned results, we hypothesize, that if COX-2, p16 and Ki67 expression is prognostic for DCIS future behaviour, the expression level of the markers correlates also with different stages of breast carcinomas such as DCIS, microinvasive cancer and early invasive cancer with an extensive intraductal compound. The aim of this study was to compare the expression of COX-2, p16 and Ki67 in different stages of breast carcinoma such as pure DCIS, microinvasive cancer (T1mic) and invasive ductal carcinoma with an extensive intraductal component (IDC with EIC). The expression was assessed only in in situ component of the three subgroups (DCIS, T1mic, EIC) in order to show a possible correlation of COX-2, p16 and Ki67 with different stages of carcinogenesis. Methods: We carried out a retrospective study using immunohistochemical staining to evaluate the expression of the markers COX-2, p16 and Ki67 in in situ lesions within three subgroups of tumors with the rising extant of invasive compound: in pure DCIS, microinvasive carcinoma (T1mic) and invasive carcinoma with extensive in situ component (IDC with EIC). Additionally, we performed a correlation analysis between the tumor subgroups and patients history data (age, parity, age of menarche, family and personal cancer history, breast feeding lengths, contraception intake, chest irradiation) as well as some of the tumor characteristics (tumor grade, multicentricity, necrosis). Results: Distribution of p16 expression differed signifi cantly among the three diagnoses. P16 score 1 was highest in the DCIS group whereas the lowest proportion was in IDC and p16 overexpression (score 2, 3) maintained this tendency (overexpression proportion in DCIS < T1mic < IDC), though this was not signifi cant. The frequency of COX-2 and p16 overexpression (phenotype COX-2+p16+) was higher in EIC within invasive carcinoma in comparison to DCIS and T1mic and was rising gradually with the severity of the diagnosis (proportion in DCIS < T1mic < IDC). Conclusion: This is the fi rst published study ever assessing the expression of COX-2, p16 and Ki67 markers in different breast tumors containing DCIS compound. Our results showed an increasing expression pattern of COX-2 and p16 with the rising severity of the diagnosis (expression was measured exclusively in in situ lesions within tumors containing different extant of invasiveness). The same relationship was showed for p16 marker alone. These data support different expression pattern of COX-2 and p16 markers in combination and p16 marker alone in "in situ lesions" according to the stage of carcinogenesis. This fact might be useful in the evaluation of further behaviour of early breast tumors (Tab. 3, Fig. 8, Ref. 29). Text in PDF www.elis.sk.
p16INK4a expression in basal-like breast carcinoma
International journal of clinical and experimental pathology, 2010
BLBC represents a distinctive group of invasive breast carcinomas with specific genotype and immunoprofile. BLBC is usually defined by gene expression profiling and is currently associated with poor outcome. BLBCs are estrogen receptor (ER) negative, progesterone receptor (PgR) negative, HER2 negative, and usually show a variable expression of basal cytokeratins (CKs), EGFR and CD117. p16(INK4a) is a tumor suppressor protein, encoded by the CDKN2A gene, which regulates cell cycle. The reported association of abnormalities in the p16/Rb pathway with increased risk of malignancy prompted us to determine the expression of p16(INK4a) in a group of BLBC; the results were compared with a group of high-grade invasive carcinoma (HG-IC) of breast. Tissue microarrays (TMA) were constructed in triplicate including 18 BLBC and 18 HG-IC. All BLBC cases were ER-/PgR-/HER2-. Seventeen (94%) BLBC were CK 5/6+/CK 14+; 14 (78%) BLCB showed EGFR expression and 13 (72%) were CD117 positive. BLBCs showe...
Estrogen receptor expression in normal breast epithelium in invasive ductal carcinoma
The European Research Journal, 2020
Objectives: Invasive ductal carcinomas (IDCs) are the most important group of malignant breast tumors and constitute 75-80% of breast carcinomas. While IDCs often present with ductal carcinoma in situ (DCIS), they sometimes include a low level of DCIS or they do not include any accompanying DCIS at all. We planned this study to compare estrogen receptor (ER) expression levels in normal mammary epithelium in IDCs with extensive DCIS (Group I) and IDCs without DCIS (Group II). Methods: Eighty IDC cases selected from among samples that were analyzed in our pathology laboratory. The cases were assessed retrospectively in light of immunohistochemical analysis results and pathology reports. Evaluation of immunohistochemistry: ER positivity in IDC was defined with a nuclear staining of more than 10% of cancer cells regardless of intensity of staining. Presence of cells showing nuclear staining for normal breast epithelium was classified in 4 groups according to their quantity and intensity. These were: 0-None: No staining was observed, 1-Single: One or two positive cells, 2-Dispersed: Dispersed positive cells surrounded by negative cells, 3-Adjoined: 10 or more positive cells contacting each other. Results: Statistically no significant difference was found between Group I and Group II in terms of ER expression. Group I were more prevalent in younger and in the premenopausal period than Group II. Conclusions: According to our study, there was no difference between Group I and Group II in terms of ER expression. But the significantly presence Group I in more young people and in premenopausal women suggests that these carcinomas develop due to high estrogen levels and that Group II develop independently than estrogen. This suggests that these groups may have different carcinogenesis and etiologies. We therefore think that this first study on IDCs with extensive DCIS and IDCs without DCIS should be supported by new research studies.
The American journal of pathology, 2017
To understand the molecular alterations driving the progression of ductal carcinoma in situ (DCIS), we compared patients with pure DCIS and patients with DCIS and synchronous invasive breast cancer (IBC). Twelve patients with extensive pure DCIS were included as a representation of indolent lesions with limited invasive capacity. These cases were matched with 12 patients with a limited DCIS component and IBC, representing lesions with a high invasive potential. Matching included age and surrogate DCIS subtypes. Gene expression profiling was performed on DCIS cells to identify transcriptional differences between these two groups. The identified genes were validated by immunohistochemistry. Nine genes showed significantly different expression. Most of these genes were highly expressed in DCIS samples with IBC, including PLAU (P = 0.002), COL1A1 (P = 0.006), KRT81 (P = 0.009), S100A7 (P = 0.015), SCGB1D2 (P = 0.023), KRT18 (P = 0.029), and NOTCH3 (P = 0.044), whereas EGFR and CXCL14 sh...
European Journal of Cancer, 1996
In order to obtain prognostic clinicopathological information, 49 cases of pure ductal carcinoma in situ of the breast (DCIS), were evaluated for the immunohistochemical expression of potential predictor markers including c-erbB-2 oncogene product, p53 protein, oestrogen (ER) and progesterone (PR) receptors, oestrogen-regulated proteins pS2 and cathepsin-D (cath-D), CD44 protein and 67-kDa laminin receptor (MLuC5). Immunohistochemical findings were compared with conventional pathological parameters, clinical findings, and the clinical outcome of the patients. When markers were matched to each other, statistical analyses provided a significant positive correlation between c-erbB-2 overexpression and ~53 positivity (P < 0.01) and between ER and PR (P < O.Ol), ER, PR and pS2 (P < O.Ol), pS2 and MLuCS (P < 0.05). Significant negative correlations between c-erbB-2 overexpression and ER (P < 0.05), PR (P < 0.01) and pS2 (P < 0.01) positivity was also observed. Data on the relationship between marker status and pathological findings revealed a significant positive trend between c-erbB-2, ~53, and increased grade values (P < 0.05) and opposite results with PR receptor expression (P < 0.01). c-erbB-2 overexpression was further significantly associated with comedotype carcinoma (P < 0.05) and distribution of disease in confluent neoplastic ducts (P < 0.01). Although no statistically significant correlation among biological markers expression, clinical findings and outcome was demonstrated, overall this study indicates that tumour cells from a subset of DCIS, which includes comedotype carcinoma, express significantly unfavourable prognostic factors.
Revista brasileira de ginecologia e obstetrícia : revista da Federação Brasileira das Sociedades de Ginecologia e Obstetrícia, 2013
PURPOSE: To compare the prognostic and predictive features between in situ and invasive components of ductal breast carcinomas. METHODS: We selected 146 consecutive breast samples with ductal carcinoma in situ (DCIS) associated with adjacent invasive breast carcinoma (IBC). We evaluated nuclear grade and immunohistochemical expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), cytokeratin 5/6 (CK5/6), and epidermal growth factor receptor (EGFR) in both components, in situ and invasive, and the Ki-67 percentage of cells in the invasive part. The DCIS and IBC were classified in molecular surrogate types determined by the immunohistochemical profile as luminal (RE/PR-positive/ HER2-negative), triple-positive (RE/RP/HER2-positive), HER2-enriched (ER/PR-negative/HER2-positive), and triple-negative (RE/RP/HER2-negative). Discrimination between luminal A and luminal B was not performed due to statistical purposes. Correlations between the categories in the two groups were made using the Spearman correlation method. RESULTS: There was a significant correlation between nuclear grade (p<0.0001), expression of RE/RP (p<0.0001), overexpression of HER2 (p<0.0001), expression of EGFR (p<0.0001), and molecular profile (p<0.0001) between components in situ and IBC. CK 5/6 showed different distribution in DCIS and IBC, presenting a significant association with the triple-negative phenotype in IBC, but a negative association among DCIS. CONCLUSIONS: Our results suggest that classical prognostic and predictive features of IBC are already determined in the preinvasive stage of the disease. However the role of CK5/6 in invasive carcinoma may be different from the precursor lesions.
Modern Pathology
The natural history of ductal carcinoma in situ (DCIS) is highly variable and difficult to predict. Biomarkers are needed to stratify patients with DCIS for adjuvant therapy. We investigated the prognostic and predictive relevance of cell cycle progression (CCP) score in women with DCIS. We measured the expression of 23 genes involved in CCP with quantitative RT-PCR on RNA extracted from formalin-fixed paraffin-embedded tumor samples, and assessed the correlation of a predefined score with histopathologic features and recurrence. The signature was analyzed in a cohort of 909 consecutive DCIS with full histopathological features treated in a single institution. The main outcome measure was ipsilateral breast event (IBE) as first event observed, be it in situ or invasive. Median follow-up time was 8.7 years (IQR 6.5-10.5 years). There were 150 ipsilateral IBEs, 84 (56%) of which were invasive. In the first 5 years of follow-up, the score provided statistically different findings (p = 0.009), with IBE rates of 14.7% (95% CI, 10.4-19.7) for the highest quartile of CCP score (Q4) and 8.7% (95% CI, 6.7-11.0) for the lowest quartiles (Q1-3). The prognostic value for IBEs approached significance also in women treated with mastectomy (adjusted hazard ratio [HR] Q4 vs. Q1-3 = 2.60; 95% CI: 0.96-7.08; P = 0.06). Radiotherapy provided a greater benefit in women with higher CCP score. In addition, Q4 predicted a different risk after tamoxifen depending on menopausal status, with a beneficial trend on IBEs in postmenopausal women (HR 0.30; 95% CI, 0.07-1.39), and an opposite trend in premenopausal women (HR 1.68; 95% CI, 0.38-7.44) (P-interaction = 0.03). The results of this study provide for the first time the evidence that CCP score is a prognostic marker, which, after additional validation, could have an important role in personalizing the management of DCIS.
Biological markers that predict clinical recurrence in ductal carcinoma in situ of the breast
European Journal of Cancer, 2003
The optimal management of ductal carcinoma in situ (DCIS) is controversial, due in part to our poor understanding of its natural history. We undertook to identify subgroups of DCIS based on the expression of biomarkers, which were related to the likelihood of clinical recurrence. Biomarker expression of a total of 95 DCIS lesions in a nested case-control study within a population-based cohort with up to 135 months follow-up data (median 101 months) was analysed using immunohistochemistry. ERBB2-positivity and bcl-2-, oestrogen receptor (ER)-and progesterone receptor (PR)-negativity were individually associated with the risk of clinical recurrence. The predictive value of these biomarkers was independent of cytonuclear grade. ERBB2, bcl-2, ER and PR expression were conserved in the recurrent lesions, including subsequent invasive cancers. p21-positive DCIS was also associated with clinical recurrence, independently of the associations with ERBB2/bcl-2/ER/PR expression. These data identify clinically and biologically relevant subcategories of DCIS lesions, an essential basis for improving management. #
Breast cancer is one of the most common malignant diseases among women in western countries. Ductal carcinoma of the breast is a pre-invasive malignant lesion that is curable. However, undetected or untreated tumors can progress to invasive breast cancer. Therefore, understanding of molecular changes in this tumor and determining of diagnostic and prognostic biomarkers will be valuable for early diagnosis and predict of prognosis in this disease. In this study, we investigated differentially expressed genes in ductal carcinoma of breast. Moreover, we also investigated probable mechanisms that abrogated in these lesions. The results have shown that there are 96 upregulated and 110 downregulated gene in ductal breast cancer compared normal breast. Analyzing of this gene list revealed that upregulated genes are significantly enriched cell cycle term. However, downregulated genes are enriched regulation of cell proliferation and apoptosis terms.
International Journal of Breast Cancer, 2011
There is a paucity of data regarding molecular subtypes of pure ductal carcinoma in situ (pDCIS). We evaluated the expression of ER, PR, HER2, Ki67, and p53 and DNA ploidy in 118 pDCIS and 100 invasive breast carcinomas (IBCAs) by routine IHC and classified them according to molecular subtypes. Quantification of biomarkers and DNA ploidy was performed by image analysis. Expression of ER, PR, and high ki67 was more frequent in pDCIS compared to IBCA. High-grade tumors had lower ER and PR expression, high Ki67, overexpression of HER2 and p53, and DNA aneuploidy. Luminal A and HER2 subtypes were more common in pDCIS, and triple negative was more prevalent in IBCA. In both groups, HER2 and triple negative subtypes were characterized by high ki67, overexpression of p53, and DNA aneuploidy compared to luminal subtypes. Molecular subtypes of IBCA are distinct from those of pDCIS. Invasion is characterized by change in phenotype in some tumors.