Germline BRCA1 Mutations and a Basal Epithelial Phenotype in Breast Cancer

Foulkes, William D.

doi:10.1093/jnci/djg050

Cited by 848 publications

(676 citation statements)

References 26 publications

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“…This was performed simply to increase the yield of high-grade, ER-negative breast carcinomas, as these are more common in the younger age group. The majority of BRCA-1-associated tumors have the basal phenotype, 8,18,19 but the BRCA-1 status was not available for any of our cases.…”

Section: Discussionmentioning

confidence: 99%

Basal phenotype of ductal carcinoma in situ: recognition and immunohistologic profile

et al. 2006

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The basal phenotype of breast carcinoma was demonstrated from a study of gene expression profiles, which demonstrated five carcinoma phenotypes with differing immunohistologic profiles and outcomes. The basal phenotype, so-named because of an immunohistologic profile that is similar to myoepithelial cells of the breast, has poor outcomes. While the invasive basal phenotype has been described, there is a paucity of literature regarding the existence or recognition of a precursor lesion. We searched our CoPath database for breast carcinomas in the age group of 37 years or less, and this yielded 98 cases from the years 2001 to April 2006. Pathology reports were screened for those cases that were negative for estrogen and progesterone receptors and HER-2/neu (triple negative). A total of 16 cases (16/98, 16%) fulfilled these criteria. Histology was reviewed and immunostains were performed for Cytokeratins 14, 17, and 5/6, vimentin, EGFR, c-kit, smooth muscle actin and p63. All 16 cases had a high-grade invasive ductal carcinoma, Nottingham score 9/9, with geographic necrosis, good circumscription and lymphoid infiltrates. Of the 16 cases, 13 exhibited at least one area of ductal carcinoma in situ (DCIS). The DCIS types were solid, flat or micropapillary, high nuclear grade, with comedonecrosis and invariably associated with intense lymphoid inflammatory cell infiltration. Of 16 invasive cases, 14 (88%) were positive for CK14, CK17, CK5/6 and EGFR; 94% were vimentin positive, while half or less of cases were positive for smooth muscle actin, c-kit or p63. All of the DCIS components demonstrated the same immunohistologic profile as the invasive component. A DCIS component of solid, flat or micropapillary type exists in the basal phenotype of breast carcinoma, and it demonstrates the same immunophenotype as the invasive carcinoma, typically positive for CK5/6, CK14, CK17, vimentin and EGFR, but negative for ER/PR and HER-2/neu.

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Section: Discussionmentioning

confidence: 99%

Basal phenotype of ductal carcinoma in situ: recognition and immunohistologic profile

et al. 2006

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“…60,70,81 Relationship between basal-like breast cancer and BRCA1 germ-line mutations There is increasing evidence to suggest a link between BRCA1 pathway and basal-like breast cancers. 82,83 The majority of tumors arising in BRCA1 germ-line mutation carriers, in particular those diagnosed before 50 years of age, have morphological features similar to those described in basal-like cancers 84,85 and show a basal-like phenotype as defined by immunohistochemistry 86,87 or expression arrays. 8 Both basal-like breast cancers and tumors arising in BRCA1 germ-line mutation carriers show a peculiar pattern of cell-cycle protein expression; 54,84,88,89 both rarely harbor CCND1 gene amplification; 54,88 however, they express significantly lower levels of p27, 84,89 and higher levels of Skp2, 84,89 cyclin E, 84,89 and caspase-3, 89 when compared with sporadic breast carcinomas and BRCA2 mutation tumors.…”

Section: S Badve Et Almentioning

confidence: 95%

Basal-like and triple-negative breast cancers: a critical review with an emphasis on the implications for pathologists and oncologists

et al. 2011

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Breast cancer is a heterogeneous disease encompassing a variety of entities with distinct morphological features and clinical behaviors. Although morphology is often associated with the pattern of molecular aberrations in breast cancers, it is also clear that tumors of the same histological type show remarkably different clinical behavior. This is particularly true for 'basal-like cancer', which is an entity defined using gene expression analysis. The purpose of this article was to review the current state of knowledge of basal-like breast cancers, to discuss the relationship between basal-like and triple-negative breast cancers, and to clarify practical implications of these diagnoses for pathologists and oncologists.

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“…Tumours arising in BRCA1 mutation carriers and Brca1 conditional knockout mice have a distinct histopathological and molecular phenotype, including high grade, high mitotic index and expression of basal and stem cell-associated genes (Lakhani et al, 1998;Sorlie et al, 2003;Liu et al, 2008;Shakya et al, 2008;Wright et al, 2008a, b). It has been suggested that BRCA1-associated tumours arise in the basal or stem cell compartments of the mammary gland (Foulkes et al, 2003), although there is also evidence to suggest that that these characteristics may arise as a consequence of BRCA1 loss in other mammary cell types (Liu et al, 2008;Smart et al, 2008). Although the detailed pathway between BRCA1 disruption and breast tumour development has yet to be fully elucidated, recent findings suggest that tumours arising in human BRCA1 mutation carriers may arise from mammary luminal progenitor cells of the mammary gland (Lim et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Analysis of Brca1-deficient mouse mammary glands reveals reciprocal regulation of Brca1 and c-kit

et al. 2010

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Disruption of the breast cancer susceptibility gene Brca1 results in defective lobular-alveolar development in the mammary gland and a predisposition to breast tumourigenesis in humans and in mice. Recent evidence suggests that BRCA1 loss in humans is associated with an expansion of the luminal progenitor cell compartment in the normal breast and tumours with a luminal progenitorlike expression profile. To further investigate the role of BRCA1 in the mammary gland, we examined the consequences of Brca1 loss in mouse mammary epithelial cells in vitro and in vivo. Here, we show that Brca1 loss is associated with defective morphogenesis of SCp2 and HC11 mouse mammary epithelial cell lines and that in the MMTV-Cre Brca1 Co/Co mouse model of Brca1 loss, there is an accumulation of luminal progenitor (CD61 þ CD29 lo CD24 þ ) cells during pregnancy. By day 1 of lactation, there are marked differences in the expression of 1379 genes, with most significantly altered pathways and networks, including lactation, the immune response and cancer. One of the most differentially expressed genes was the luminal progenitor marker, c-kit. Immunohistochemical analysis revealed that the increase in c-kit levels is associated with an increase in c-kit positivity. Interestingly, an inverse association between Brca1 and c-kit expression was also observed during mammary epithelial differentiation, and small interfering RNA-mediated knockdown of Brca1 resulted in a significant increase in c-kit mRNA levels. We found no evidence that c-kit plays a direct role in regulating differentiation of HC11 cells, suggesting that Brca1-mediated induction of c-kit probably contributes to Brca1-associated tumourigenesis via another cellular process, and that c-kit is likely to be a marker rather than a mediator of defective lobular-alveolar development resulting from Brca1 loss.

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Germline BRCA1 Mutations and a Basal Epithelial Phenotype in Breast Cancer

Cited by 848 publications

References 26 publications

Basal phenotype of ductal carcinoma in situ: recognition and immunohistologic profile

Basal phenotype of ductal carcinoma in situ: recognition and immunohistologic profile

Basal-like and triple-negative breast cancers: a critical review with an emphasis on the implications for pathologists and oncologists

Analysis of Brca1-deficient mouse mammary glands reveals reciprocal regulation of Brca1 and c-kit

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