PERSPECTIVE Carcinogenesis of Breast Cancer: Advances and Applications (original) (raw)
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Role of the Brk tyrosine kinase in breast cancer progression
Breast Cancer Research, 2006
Background Epidemiological studies have shown that only about 20% of the familial clustering of breast cancer is explained by the known highly penetrant mutations in BRCA1 and BCRA2. We have set out to search for the genes for the remaining 80%. Twin studies indicate a predominant role of shared genes rather than a shared environment; the patterns of occurrence of breast cancer in families are consistent with a major polygenic component. Methods We have assembled a population based set of 5,000 breast cancer cases and 5,000 controls from the East Anglian population. We have simple clinical and epidemiological information, including family history, and samples of blood and paraffin embedded tumour. We have used association studies based on single nucleotide polymorphisms, first with candidate genes and then in a genome-wide scan of 266,000 single nucleotide polymorphisms, to search for the putative predisposing genes. We have as yet searched only for common variants (frequency >5%). Results We have modelled the effects of polygenic predisposition in the East Anglian population, and have shown that the model predicts a wide distribution of individual risk in the population, such that half of all breast cancers may occur in the 12% of women at greatest risk. Both the candidate gene-based and genome-wide scans have provided provisional identification of a number of novel susceptibility genes, and these are currently being confirmed by a worldwide consortium of independent laboratories totalling 20,000-plus cases and controls. No single gene so far identified contributes more than 2% of the total inherited component, consistent with a model in which susceptibility is the result of a large number of individually small genetic effects. S2 Translating breast cancer research into clinical practice-new approaches and better outcomes
Expression of the HER 1-4 family of receptor tyrosine kinases in breast cancer. Commentary
Journal of Pathology, 2003
EGFr/HER1 and c-erbB-2/HER2 expression are associated with poor prognosis in breast cancer. The type I receptor tyrosine kinase (RTK) family to which they belong has four members (HER1-4). In this study, expression of HER1-4 and oestrogen receptor (ER) expression were determined by immunohistochemistry in 220 breast carcinomas. Elevated expression of HER1was observed in 16.4%, HER2 in 22.8%, HER3 in 17.5%, and HER4 in 11.9% of these tumours. Patients whose tumours overexpressed HER1, 2 or 3 had reduced survival (p =< 0.001), whereas those whose tumours overexpressed HER4 had increased survival (p = 0.013); 38.6% of cases overexpressed one or more of HER1, 2 or 3. HER4 was rarely overexpressed with other HERs (1.4% of cases). Cox's multiple regression analysis demonstrated that overexpression of HER1/2/3, HER4, and standard prognostic indicators independently affected survival. HER1-3 expression was related to ER negativity (p < 0.0001, χ 2 ). Patients with ER-positive, HER1-3-positive tumours had a significantly poorer survival (p < 0.001) than those with ER-positive/HER-negative or HER4-positive tumours. Expression of HER RTKs displays complex interactions between different family members. There is a strong interaction, in terms of survival, between HER expression and ER expression. The development of HER-targeted agents (eg Herceptin, Iressa), and agents targeted at the downstream signalling pathways, therefore provides new possibilities in the treatment of breast cancer.
Oncogene, 2002
Mutational inactivation of BRCA1 confers increased risk for breast cancer. However, the underlying basis for the breast tissue-restricted, tumor-suppressive properties of BRCA1 remains poorly defined. Here, we show that BRCA1 and the estrogen receptor a (ER-a) modulated vascular endothelial growth factor (VEGF) gene transcription and secretion in breast cancer cells. ERa interacted in vitro and in vivo with BRCA1, and this interaction was mediated by the AF-2 domain of ERa and two domains of BRCA1, the amino-acid residues 1-306 and 428-683. Endogenous interaction of ERa with BRCA1 was observed in normal MCF-10A breast epithelial cells and in breast cancer cells (MCF-7 and T47D), and this interaction was significantly reduced in the presence of estrogen. Furthermore, ERa induced activation of VEGF gene transcription, using human VEGF promoter-luciferase reporter constructs. The AF-2 domain of ERa was also shown to induce VEGF gene transcription activation similar to that obtained with the full-length ERa. However, in the presence of BRCA1, VEGF gene transcription activation and VEGF protein secretion were significantly inhibited in a dose-dependent manner. The BRCA1 domain of 1-683 amino acid residues was required for this inhibition of VEGF gene transcription activation. Three mutated forms of BRCA1 (A1708E, M1775R and Y1853X), that have been identified in familial breast cancers, failed to associate with ERa and to suppress VEGF promoter activity and VEGF protein secretion. Overexpression of wild-type BRCA1 in HCC-1937 breast cancer cells that lack endogenous functional BRCA1 significantly reduced VEGF secretion in these cells. These results demonstrate a novel pathogenic mechanism whereby mutations in BRCA1, via their interaction with ERa , could promote tumorigenesis through the hormonal regulation of mammary epithelial cell proliferation and impaired VEGF function, which may lead to cancer growth and angiogenesis.
Expression of the HER1–4 family of receptor tyrosine kinases in breast cancer
The Journal of Pathology, 2003
EGFr/HER1 and c-erbB-2/HER2 expression are associated with poor prognosis in breast cancer. The type I receptor tyrosine kinase (RTK) family to which they belong has four members (HER1-4). In this study, expression of HER1-4 and oestrogen receptor (ER) expression were determined by immunohistochemistry in 220 breast carcinomas. Elevated expression of HER1was observed in 16.4%, HER2 in 22.8%, HER3 in 17.5%, and HER4 in 11.9% of these tumours. Patients whose tumours overexpressed HER1, 2 or 3 had reduced survival (p =< 0.001), whereas those whose tumours overexpressed HER4 had increased survival (p = 0.013); 38.6% of cases overexpressed one or more of HER1, 2 or 3. HER4 was rarely overexpressed with other HERs (1.4% of cases). Cox's multiple regression analysis demonstrated that overexpression of HER1/2/3, HER4, and standard prognostic indicators independently affected survival. HER1-3 expression was related to ER negativity (p < 0.0001, χ 2 ). Patients with ER-positive, HER1-3-positive tumours had a significantly poorer survival (p < 0.001) than those with ER-positive/HER-negative or HER4-positive tumours. Expression of HER RTKs displays complex interactions between different family members. There is a strong interaction, in terms of survival, between HER expression and ER expression. The development of HER-targeted agents (eg Herceptin, Iressa), and agents targeted at the downstream signalling pathways, therefore provides new possibilities in the treatment of breast cancer.
2014
Abstract: Breast cancers expressing estrogen receptor α, progesterone receptor, or the human epidermal growth factor receptor 2 (HER2) proto-oncogene account for approximately 90% of cases, and treatment with antiestrogens and HER2-targeted agents has resulted in drastically improved survival in many of these patients. Read this review and sign up to receive Pharmacogenomics and Personalized Medicine journal here: http://www.dovepress.com/articles.php?article\_id=17849
Clinical Cancer Research, 2013
Purpose: Mutations in receptor tyrosine kinase (RTK) genes can confer resistance to receptor-targeted therapies. A T798M mutation in the HER2 oncogene has been shown to confer resistance to the tyrosine kinase inhibitor (TKI) lapatinib. We studied the mechanisms of HER2-T798M-induced resistance to identify potential strategies to overcome that resistance. Experimental Design: HER2-T798M was stably expressed in BT474 and MCF10A cells. Mutant cells and xenografts were evaluated for effects of the mutation on proliferation, signaling, and tumor growth after treatment with combinations of inhibitors targeting the EGFR/HER2/HER3/PI3K axis. Results: A low 3% allelic frequency of the T798M mutant shifted 10-fold the IC 50 of lapatinib. In mutantexpressing cells, lapatinib did not block basal phosphorylation of HER2, HER3, AKT, and ERK1/2. In vitro kinase assays showed increased autocatalytic activity of HER2-T798M. HER3 association with PI3K p85 was increased in mutant-expressing cells. BT474-T798M cells were also resistant to the HER2 antibody trastuzumab. These cells were sensitive to the pan-PI3K inhibitors BKM120 and XL147 and the irreversible HER2/EGFR TKI afatinib but not the MEK1/2 inhibitor CI-1040, suggesting continued dependence of the mutant cells on ErbB receptors and downstream PI3K signaling. BT474-T798M cells showed increased expression of the EGFR ligands EGF, TGFa, amphiregulin, and HB-EGF. Addition of the EGFR neutralizing antibody cetuximab or lapatinib restored trastuzumab sensitivity of BT474-T798M cells and xenografts, suggesting that increased EGFR ligand production was causally associated with drug resistance. Conclusions: Simultaneous blockade of HER2 and EGFR should be an effective treatment strategy against HER2 gene-amplified breast cancer cells harboring T798M mutant alleles. Clin Cancer Res; 19(19); 5390-401. Ó2013 AACR.
The classification of invasive breast cancer currently involves the assessment of histological criteria including both morphology-based and immunohistochemical (IHC) analysis. The vast majority of breast carcinomas (~70-80%) are described as "invasive ductal carcinomas not otherwise specified" (IDC-NOS) based on architectural patterns and cytological features. In contrast, around 15% of breast cancers are lobular (Ellis., 2003). In addition to histological tumor type, tumor grade is the other important intrinsic characteristic that can be assessed by histopathological analysis. Tumor grade is an assessment of differentiation (tubule formation and nuclear pleomorphism) and proliferative activity (mitotic index), allowing tumors to be further stratified and providing key prognostic information (Rakha et al., 2010). Traditional pathological parameters such as histological type, tumor size, histological grade and axillary lymph-node involvement have been shown to correlate with clinical outcome and provide the basis for prognostic evaluation (Elston et al., 1999). IHC markers such as the expression of hormone receptors (estrogen (ER) and progesterone receptors (PR)) and the overexpression and/or amplification of the human epidermal growth factor receptor 2 (HER2) provide additional therapeutic predictive value and are of key importance in guiding treatment selection (Harris et al., 2007). Hormone receptor-positive breast cancers account for around 75-80% of all cases. Standardized IHC assays for the routine testing of ER and PR are PR-positive tumors with negative HER2 and low Ki67 (proliferating cell nuclear antigen) index by immunohistochemistry (Carey et al., 2006). Luminal B tumors comprise 15%-20% of breast cancers (Creighton et al., 2012). From the immunohistochemical point of view are defined as ER-positive, HER2-negative and Ki67 high or ER and HER-2 positive tumors (Yersal and Barutca, 2014). This subtype has a higher recurrence rate and lower survival rates after relapse compared to Luminal A subtype (Ellis et al., 2008). Luminal tumors respond well to hormone therapy but poorly to conventional chemotherapy (Brenton et al., 2005). Treatment response differs between luminal subtypes. Thus, Luminal A tumors could be adequately treated with endocrine therapy, while Luminal B tumors which The basal subtype is composed of triple negative (ER-PR-HER2-) tumors with expression profiles mimicking that of the basal epithelial cells of other parts of the body and normal breast myoepithelial cells (Perou et al., 2000). Such expression patterns include lacking or low expression of hormone receptors and HER2, and high expression of basal markers (such as keratins 5, 6, 14, 17, EGFR) and proliferation related genes (Perou et al., 2000). These tumors are of particular interest because they follow aggressive clinical course and currently lack any form of standard targeted systemic therapy. Basal tumors are It has come to light that cancer cells are able to become resistant to therapies by recruiting the use of a similar, compensatory pathway that continue downstream activation of protein synthesis. This mechanism is referred to as crosstalk between two pathways to allow continued cancer cell growth and survival. An important trait of the Erbb family is the activation of the PI3K and the MAPK pathways. HER2-mediated activation of PI3K causes the phosphorylation of the serine/threoninespecific protein kinase, AKT, which in turn activates mTOR, able to induce protein synthesis that stimulates cell proliferation, migration, and metabolism (Altomare and Testa, 2005). Alterations in breast cancer resulting in hyperactivity of the PI3K pathway include gain-of-function mutations in PIK3CA (the gene encoding the PI3K catalytic subunit p110α), (Campbell et al., 2004; Bachman et al., 2004), mutations in AKT1 (Carpten et al., 2007), amplifications of AKT2 (Bellacosa et al., 1995), loss of the PTEN lipid phosphatase (Li et al., 1997; Saal et al., 2007) and loss of the tumor suppressor INPP4B (inositol polyphosphate 4-phosphatase type II) (Gewinneret al., 2009). Due to role of AKT in a variety of human solid tumors and hematological malignancies, several therapies have been developed to target components of the AKT pathway