The BRG1 chromatin remodeler protects against ovarian cysts, uterine tumors, and mammary tumors in a lineage-specific manner.

Daniel W Serber,Terry Van Dyke,Connie J Eaves,Maisam Makarem,Gary B Rosson,Virginia Godfrey,Karl Simin,Allison Rogala,Scott J Bultman,Toshi Shioda

doi:10.1371/journal.pone.0031346

Daniel W Serber, Terry Van Dyke + Show 8 more

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https://doi.org/10.1371/journal.pone.0031346

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Abstract

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 (Brg1null/+) 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 Brg1Wap-Cre conditional homozygotes lactated normally and did not develop mammary tumors even when they were maintained on a Brm-deficient background. However, Brg1Wap-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.

Highlights

Mammalian SWI/SNF chromatin-remodeling complexes regulate many cellular processes and function as tumor suppressors
Brg1 and Brm are co-expressed in all mammary epithelial cells, whereas Whey acidic protein (Wap) expression is confined to the luminal cells of the mammary gland in pregnant mice
In a first series of experiments, we sought to characterize the expression of Brg1, Brm, and Wap in different subsets of mammary cells in normal adult virgin and pregnant female mice

Summary

Introduction

Mammalian SWI/SNF chromatin-remodeling complexes regulate many cellular processes and function as tumor suppressors. Several SWI/SNF subunits have been shown to physically interact with known tumor-suppressor genes and proto-oncogenes or their encoded proteins [1,2,3]. These studies include the demonstrated ability of the BRG1 catalytic subunit ( known as SMARCA4) and SNF5 ( known as BRG1associated factor 47 or BAF47) to bind to the promoters of the p15INK4b (known as p19 in the mouse), p16INK4a, and p21CIP1/WAF1 cyclin-dependent kinase (CDK) inhibitors and activate expression of these target genes [6,7,8,9,10]. BRG1 and an alternative catalytic subunit, BRM ( known as SMARCA2), can bind to hypophosphorylated RB and are required to repress the activity of E2F1, inhibit the transcription of cyclins A and E, and mediate G1 cell-cycle arrest [11,12,13,14,15]

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