Analysis of Brca1-deficient mouse mammary glands reveals reciprocal regulation of Brca1 and c-kit
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 prog...
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Veröffentlicht in: | Oncogene 2011-03, Vol.30 (13), p.1597-1607 |
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Zusammenfassung: | 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. |
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ISSN: | 0950-9232 1476-5594 |
DOI: | 10.1038/onc.2010.538 |