title: The BRG1 chromatin remodeler protects against ovarian cysts, uterine tumors, and mammary tumors in a lineage-specific manner.
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 (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.
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Serber
authors.forename: Allison
authors.initials: A
authors.lastname: Rogala
authors.forename: Maisam
authors.initials: M
authors.lastname: Makarem
authors.forename: Gary B
authors.initials: GB
authors.lastname: Rosson
authors.forename: Karl
authors.initials: K
authors.lastname: Simin
authors.forename: Virginia
authors.initials: V
authors.lastname: Godfrey
authors.forename: Terry
authors.initials: T
authors.lastname: Van Dyke
authors.forename: Connie J
authors.initials: CJ
authors.lastname: Eaves
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Bultman
mesh_terms: D000818:Animals; D017209:Apoptosis; D019070:Cell Lineage; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D042002:Chromatin Assembly and Disassembly; D004265:DNA Helicases / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D006801:Humans; D019426:Integrases / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000378:metabolism / Q000473:pathology; D015674:Mammary Neoplasms, Animal / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008894:Milk Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D010048:Ovarian Cysts / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D010641:Phenotype; D011247:Pregnancy; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D014594:Uterine Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control*
chemical_list: D008894:Milk Proteins; D009687:Nuclear Proteins; D016160:Retinoblastoma Protein; C499503:Smarca2 protein, mouse; D014157:Transcription Factors; C024471:whey acidic proteins; C045073:Cre recombinase; D019426:Integrases; C513194:Smarca4 protein, mouse; D004265:DNA Helicases