Abstract
BRCA1 mutation carriers are predisposed to developing basal-like breast cancers with high metastasis and poor prognosis. Yet, how BRCA1 suppresses formation of basal-like breast cancers is still obscure. Deletion of p18(Ink4c) (p18), an inhibitor of CDK4 and CDK6, functionally inactivates the RB pathway, stimulates mammary luminal stem cell (LSC) proliferation, and leads to spontaneous luminal tumor development. Alternately, germline mutation of Brca1 shifts the fate of luminal cells to cause luminal-to-basal mammary tumor transformation. Here, we report that disrupting Brca1 by either germline or epithelium-specific mutation in p18-deficient mice activates epithelial-to-mesenchymal transition (EMT) and induces dedifferentiation of LSCs, which associate closely with expansion of basal and cancer stem cells and formation of basal-like tumors. Mechanistically, BRCA1 bound to the TWIST promoter, suppressing its activity and inhibiting EMT in mammary tumor cells. In human luminal cancer cells, BRCA1 silencing was sufficient to activate TWIST and EMT and increase tumor formation. In parallel, TWIST expression and EMT features correlated inversely with BRCA1 expression in human breast cancers. Together, our findings showed that BRCA1 suppressed TWIST and EMT, inhibited LSC dedifferentiation, and repressed expansion of basal stem cells and basal-like tumors. Thus, our work offers the first genetic evidence that Brca1 directly suppresses EMT and LSC dedifferentiation during breast tumorigenesis.
Highlights
Mammary luminal and basal epithelial cells originate from multipotent progenitors in the embryo [1,2], and expansion and maintenance of these cells in adults are ensured by unipotent luminal stem cells (LSC) and basal stem cells (BSC), respectively [1, 3]
Prompted by the highly invasive heterogeneous mammary tumors developed in p18À/À; Brca1þ/À mice with various degrees of whorls and clusters of spindle-shaped cells within these tumors—typical morphologic characteristics of mesenchymal cells [10]—we looked at molecular markers associated with epithelial-to-mesenchymal transition (EMT)
Expression, expansion of BSCs and Cancer stem cells (CSC), and induction of EMT and basal-like tumors. These results suggest that either germline mutation of Brca1 or mammary epithelia-specific deletion of Brca1 is responsible for the activation of EMT-inducing transcription factors (EMT-TF), induction of EMT, dedifferentiation of LSCs, expansion of BSCs and CSCs as well as the development of basal-like tumors
Summary
Mammary luminal and basal epithelial cells originate from multipotent progenitors in the embryo [1,2], and expansion and maintenance of these cells in adults are ensured by unipotent luminal stem cells (LSC) and basal stem cells (BSC), respectively [1, 3]. Cancer stem cells (CSC) are a subpopulation of cancer cells that shares characteristics with stem cells such as self-renewal ability and mutipotency. CSCs could generate daughter cells, contributing to tumor growth, and are associated with radioresistance and chemoresistance, metas-. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). F. Bai and H.L. Chan contributed to this article
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