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The BRG1 catalytic subunit of SWI/SNF-related complexes is required for mammalian development as exemplified by the early embryonic lethality of  Brg1  null homozygous mice. BRG1 is also a tumor suppressor and, in mice, 10% of heterozygous ( Brg1 null/+  ) females develop mammary tumors. We now demonstrate that BRG1 mRNA and protein are expressed in both the luminal and basal cells of the mammary gland, raising the question of which lineage requires BRG1 to promote mammary homeostasis and prevent oncogenic transformation. To investigate this question, we utilized  Wap-Cre  to mutate both  Brg1  floxed alleles in the luminal cells of the mammary epithelium of pregnant mice where WAP is exclusively expressed within the mammary gland. Interestingly, we found that  Brg1 Wap-Cre   conditional homozygotes lactated normally and did not develop mammary tumors even when they were maintained on a  Brm -deficient background. However,  Brg1 Wap-Cre   mutants did develop ovarian cysts and uterine tumors. Analysis of these latter tissues showed that both, like the mammary gland, contain cells that normally express  Brg1  and  Wap . Thus, tumor formation in  Brg1  mutant mice appears to be confined to particular cell types that require BRG1 and also express  Wap . Our results now show that such cells exist both in the ovary and the uterus but not in either the luminal or the basal compartments of the mammary gland. Taken together, these findings indicate that SWI/SNF-related complexes are dispensable in the luminal cells of the mammary gland and therefore argue against the notion that SWI/SNF-related complexes are essential for cell survival. These findings also suggest that the tumor-suppressor activity of BRG1 is restricted to the basal cells of the mammary gland and demonstrate that this function extends to other female reproductive organs, consistent with recent observations of recurrent  ARID1A/BAF250a  mutations in human ovarian and endometrial tumors.

The BRG1 Chromatin Remodeler Protects Against Ovarian Cysts, Uterine Tumors, and Mammary Tumors in a Lineage-Specific Manner