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The cancer stem cell hypothesis proposes that tumors contain a subset of stem or progenitor cells that are resistant to chemotherapy and have evaded the normally tight control of self-renewal. BRCA1 is known to play an essential role in cancer stem cell maintenance and differentiation. In fact, breast tissue from women with germline mutations in BRCA1 show regions of increased ALDH1 positivity, a marker of stem cells. Furthermore, knockdown of BRCA1 in normal tissue from reduction mammoplasty leads to increased ALDH1 and increased stem cell number as assessed by mammosphere formation.
Activin B is a secreted protein that is a member of the TGFβ family. It is a homodimer of inhibin βB that is expressed in various tissues and has numerous functions, including regulation of gonadal function, proliferation, metastasis, differentiation and stem cell maintenance.
Inhibin βB was identified as a transcriptional target of BRCA1 in SKBR7 cells on an Almac Breast-specific microarray. The target was analysed in several breast cell lines and shown to be repressed in basal-like, but not luminal, cell lines following BRCA1 knockdown or reconstitution. Chromatin immunoprecipitation analysis showed that BRCA1 is present on the INHBB promoter. Furthermore, loss of BRCA1 reduced the amount of secreted protein, which in turn correlated with reduced activation of the TGFβ pathway as shown by reduced phosphorylation of Smad2.
We have stably knocked down BRCA1 in MCF10A cells which, as expected, increased stem cell numbers in comparison with control cells as assessed by mammosphere formation and Aldefluor postivity. This defect can be rescued by addition of recombinant activin B or mimicked by inhibiting activin B activity with follistatin or SB-431542.
We have identified inhibin βB as a novel transcriptional target of BRCA1 in basal-like cell lines. Preliminary phenotypic studies indicate that the homodimer of inhibin βB, activin B, functions downstream of BRCA1 in regulating stem cell numbers.