Analysis of brca1-deficient mouse mammary glands reveals reciprocal regulation of Brca1 and c-kit

Smart, C.E., Wronski, A., French, J.D., Edwards, S.L., Asselin-Labat, M.L., Waddell, N., Peters, K., Brewster, B.L., Brooks, K., Simpson, K., Manning, N., Lakhani, S.R., Grimmond, S., Lindeman, G.J., Visvader, J.E. and Brown, M.A. (2011) Analysis of brca1-deficient mouse mammary glands reveals reciprocal regulation of Brca1 and c-kit. Oncogene, 30 13: 1597-1607. doi:10.1038/onc.2010.538


Author Smart, C.E.
Wronski, A.
French, J.D.
Edwards, S.L.
Asselin-Labat, M.L.
Waddell, N.
Peters, K.
Brewster, B.L.
Brooks, K.
Simpson, K.
Manning, N.
Lakhani, S.R.
Grimmond, S.
Lindeman, G.J.
Visvader, J.E.
Brown, M.A.
Title Analysis of brca1-deficient mouse mammary glands reveals reciprocal regulation of Brca1 and c-kit
Journal name Oncogene   Check publisher's open access policy
ISSN 0950-9232
Publication date 2011-03
Year available 2010
Sub-type Article (original research)
DOI 10.1038/onc.2010.538
Volume 30
Issue 13
Start page 1597
End page 1607
Total pages 11
Place of publication United Kingdom
Publisher Nature Publishing Group
Collection year 2011
Language eng
Formatted abstract 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 Brca1Co/Co mouse model of Brca1 loss, there is an accumulation of luminal progenitor (CD61+CD29loCD24+) 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.Oncogene advance online publication, 6 December 2010; doi:10.1038/onc.2010.538.
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Created: Tue, 22 Feb 2011, 10:17:38 EST by Assoc Prof Melissa Brown on behalf of School of Chemistry & Molecular Biosciences