c-Kit is required for growth and survival of the cells of origin of Brca1-mutation-associated breast cancer

Oncogene. 2012 Feb 16;31(7):869-83. doi: 10.1038/onc.2011.289. Epub 2011 Jul 18.


BRCA1 mutation-associated breast cancer originates in oestrogen receptor-alpha-negative (ER(-)) progenitors in the mammary luminal epithelium. These cells also express high levels of the Kit gene and a recent study demonstrated a correlation between Brca1 loss and Kit over-expression in the mammary epithelium. However, the functional significance of c-Kit expression in the mammary gland is unknown. To address this, c-Kit(-) and c-Kit(+) mammary epithelial subsets were isolated by flow cytometry, characterised for expression of lineage-specific cell markers and functionally analysed by in vitro colony forming and in vivo transplantation assays. The results confirm that the majority of luminal ER(-) progenitors are c-Kit(+), but also that most stem cells and the differentiated cell populations are c-Kit(-). A subset of c-Kit(+) cells with high proliferative potential was found in the luminal ER(+) population, however, suggesting the existence of a distinct luminal ER(+) progenitor cell type. Analysis of mouse Brca1 mammary tumours demonstrated that they expressed Kit and its downstream effector Lyn at levels comparable to the most strongly c-Kit(+) luminal ER(-) progenitors. Consistent with c-Kit being a progenitor cell marker, in vitro three-dimensional differentiation of c-Kit(+) cells resulted in a loss of c-Kit expression, whereas c-Kit over-expression prevented normal differentiation in vivo. Furthermore, c-Kit was a functional marker of proliferative potential, as c-Kit inhibition by short hairpin knockdown prevented normal epithelial growth and caused cells to undergo apoptosis. Therefore, c-Kit defines distinct progenitor populations in the mammary epithelium and is critical for mammary progenitor survival and proliferation. Importantly, c-Kit is only the second mammary epithelial stem/progenitor marker to be shown to have a functional role in the mammary epithelium and the first marker to be shown to be required for progenitor cell function. The c-Kit signalling network has potential as a target for therapy and/or prevention in BRCA1-associated breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • BRCA1 Protein / genetics*
  • BRCA1 Protein / metabolism
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Differentiation / genetics
  • Cell Proliferation*
  • Cell Survival / genetics
  • Cells, Cultured
  • Epithelial Cells / metabolism
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mammary Glands, Animal / cytology
  • Mammary Glands, Animal / metabolism
  • Mammary Neoplasms, Experimental / genetics
  • Mammary Neoplasms, Experimental / metabolism
  • Mammary Neoplasms, Experimental / pathology
  • Mice
  • Mutation*
  • NIH 3T3 Cells
  • Proto-Oncogene Proteins c-kit / genetics*
  • Proto-Oncogene Proteins c-kit / metabolism
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / genetics
  • Stem Cells / metabolism


  • BRCA1 Protein
  • Estrogen Receptor alpha
  • Proto-Oncogene Proteins c-kit