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

C. E. Smart, A. Wronski, J. D. French, S. L. Edwards, M. L. Asselin-Labat, N. Waddell, K. Peters, B. L. Brewster, K. Brooks, K. Simpson, N. Manning, S. R. Lakhani, S. Grimmond, G. J. Lindeman, J. E. Visvader, M. A. Brown

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


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 progenitor-like 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 CD29 lo CD24 ) 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.

Original languageEnglish (US)
Pages (from-to)1597-1607
Number of pages11
Issue number13
StatePublished - Mar 31 2011
Externally publishedYes


  • Brca1
  • c-kit
  • expression profiling
  • luminal progenitor
  • mammary epithelial morphogenesis
  • mammary gland

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research


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