BRCA1 regulates human mammary stem/progenitor cell fate

Abstract

Although it is well established that women with germ-line mutations in the BRCA1 gene have a greatly increased lifetime incidence of breast and ovarian cancer, the molecular mechanisms responsible for this tissue-specific carcinogenesis remain undefined. The majority of these breast cancers are of the basal-like phenotype characterized by lack of expression of ER, PR, and ERBB2. Because this phenotype has been proposed to resemble that of normal breast stem cells, we examined the role of BRCA1 in human mammary stem cell fate. Using both in vitro systems and a humanized NOD/SCID mouse model, we demonstrate that BRCA1 expression is required for the differentiation of ER-negative stem/ progenitor cells to ER-positive luminal cells. Knockdown of BRCA1 in primary breast epithelial cells leads to an increase in cells displaying the stem/progenitor cell marker ALDH1 and a decrease in cells expressing luminal epithelial markers and estrogen receptor. In breast tissues from women with germ-line BRCA1 mutations, but not normal controls, we detect entire lobules that, although histologically normal, are positive for ALDH1 expression but are negative for the expression of ER. Loss of heterozygosity for BRCA1 was documented in these ALDH1-positive lobules but not in adjacent ALDH1-negative lobules. Taken together, these studies demonstrate that BRCA1 plays a critical role in the differentiation of ER-negative stem/progenitor cells to ER-positive luminal cells. Because BRCA1 also plays a role in DNA repair, our work suggests that loss of BRCA1 may result in the accumulation of genetically unstable breast stem cells, providing prime targets for further carcinogenic events.breast cancer ͉ stem cell ͉ hereditary cancer A ccumulating evidence has provided support for the cancer stem cell hypothesis, which holds that cancers originate in tissue stem and/or progenitor cells through the dysregulation of self-renewal processes. The ensuing tumors are driven by a cellular subcomponent that retains stem cell properties (1). Evidence for a cancer stem cell component has been generated in human breast cancers (2), as well as cancers of hematopoietic and solid tumor origin (3-6). A number of developmental pathways such as NOTCH (7), Hedgehog (8,9), and Wnt (9, 10) have been shown to be involved in the regulation of self-renewal and the differentiation of stem and progenitor cells in a number of cell types. Furthermore, these pathways are frequently dysregulated during carcinogenesis (9-13). It is not known whether genes that contribute to hereditary cancers play a role in regulating stem cell fate. Heterozygous germ-line mutations in the BRCA1 gene predispose women to breast and ovarian cancer with a lifetime risk of breast cancer of up to 85% (14). The vast majority of breast tumors in these patients display a basal-like phenotype characterized by a lack of expression of ER, PR, and ERBB2, but robust expression of markers of myoepithelial differentiation (15). Mouse models using conditional BRCA1 KOs have suggested an important role for ...

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

“…These observations support the finding that Brca1-deficient ER-negative primary mammary progenitor cells are defective in their ability to differentiate into ER-positive luminal cells in vitro (Liu et al, 2008) and that aberrant luminal progenitor cells are expanded in breast tissue from human BRCA1 mutation carriers (Lim et al, 2009) …”

“…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).…”

Epithelial-Mesenchymal Transition (EMT) in Tumor-Initiating Cells and Its Clinical Implications in Breast Cancer

“…Of the canonical pathways from Ingenuity Pathway Analysis represented by our own TIC gene signature, Notch was one of the top upregulated pathways. Recent evidence also suggest that both hereditary breast cancers in BRCA1 carriers [46], as well as sporadic breast cancers driven by HER2 amplification, may result from dysregulation of stem cell self-renewal pathways. Our preliminary data from a neoadjuvant lapatinib study suggests that breast cancer stem cells are relatively resistant the chemotherapy, but are affected by the EGFR/HER2 inhibitor lapatinib [5].…”

The role of early life genistein exposures in modifying breast cancer risk

“…The hormonal environment associated with these stages might affect breast cancer risk by increasing or reducing the total number of replicating stem cells, their lineagespecific differentiation to myoepithelial and luminal cells, and eventually the number of cells at risk for malignant transformation (Trichopoulos et al, 2005). There is accumulating evidence for the hypothesis that breast cancer risk is determined in part by the number of susceptible breast stem/progenitor cells that can serve as targets for transformation (Liu et al, 2008).…”