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

Regan, J. L., Kendrick, Howard, Magnay, F.-A., Vafaizadeh, V., Groner, B. and Smalley, Matthew ORCID: 2012. c-Kit is required for growth and survival of the cells of origin of Brca1-mutation-associated breast cancer. Oncogene 31 (7) , pp. 869-883. 10.1038/onc.2011.289

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
European Cancer Stem Cell Research Institute (ECSCRI)
Subjects: Q Science > QH Natural history > QH426 Genetics
R Medicine > R Medicine (General)
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Uncontrolled Keywords: Brca1; c-Kit; mammary; progenitor
Publisher: Nature Publishing
ISSN: 0950-9232
Last Modified: 22 Jun 2023 10:01

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