Project description:Clinical studies have linked use of progestins (synthetic progesterone (P4)) to breast cancer risk. However, little is understood regarding the role native P4, signaling through the progesterone receptor (PR), plays in formation of breast tumors. Studies published by our lab highlighted a link between PR and immune signaling pathways, suggesting PR induces PR to repress the interferon signaling pathway. Given these findings, we sought to investigate whether P4/PR drive immunomodulation in the mammary gland and development of mammary gland tumors. We found that mice treated with P4 displayed changes in the mammary gland suggesting inhibited immune response compared to placebo-treated mice. Furthermore, transgenic mice with PR overexpression demonstrated decreased numbers of immune cell populations in their mammary gland, lymph nodes, and spleens. Upon long-term monitoring, we determined that multi-parous PR overexpressing mice developed significantly more mammary gland tumors than control mice. Additionally, tumors of PR overexpressing mice contained fewer infiltrating immune cells. Finally, RNA sequencing analysis of tumor samples revealed that immune-related gene signatures were enriched in tumors of control mice compared to tumors of PR overexpressing mice. Together, these findings provide a novel mechanism behind P4-mediated promotion of mammary gland tumor development and provide rationale to investigate anti-progestin treatment to promote immune-mediated elimination of mammary gland tumors.
Project description:Progesterone (P) acting through its cognate nuclear receptors (PRs) plays an essential role in driving pregnancy-associated branching morphogenesis of the mammary gland. However, the fundamental mechanisms, including global cistromic and acute genomic transcriptional responses that are required to elicit active branching morphogenesis in response to P, have not been elucidated. We used microarray analysis to identify global gene expression signatures that are acutely regulated by PRs in the mouse mammary gland after acute P treatment. Mammary gland gene expression data from 10-week-old ovariectomized wildtype and progesterone receptor null mice treated subcutaneously with 17β-Estradiol for 24 hours and then 17β-Estradiol plus Progesterone for 8 or 24 hours. Three replicate pools were tested with three mice per pool.
Project description:The present experiments were performed to determine the roles of estrogen receptors α and β (ERα and ERβ) in normal and neoplastic development in the mouse mammary gland. In wild-type mice, in vivo administration of estradiol (E) + progesterone (P) stimulated mammary ductal growth and alveolar differentiation. Mammary glands from mice in which the ERβ gene has been deleted (βERKO mice) demonstrated normal ductal growth and differentiation in response to E + P. By contrast, mammary glands from mice in which the ERα gene has been deleted (αERKO mice) demonstrated only rudimentary ductal structures that did not differentiate in response to E + P. EGF demonstrates estrogen-like activity in the mammary glands of αERKO mice: treatment of αERKO mice with EGF + P (without E) supported normal mammary gland development, induced expression of progesterone receptor (PR), and increased levels of G- protein-coupled receptor (GPR30) protein. Mammary gland development in βERKO mice treated with EGF + P was comparable to that of wild-type mice receiving EGF + P; EGF had no statistically significant effects on the induction of PR or expression of GPR30 in mammary glands harvested from either wild-type mice or βERKO mice. In vitro exposure of mammary glands to 7,12-dimethylbenz[a]anthracene (DMBA) induced preneoplastic mammary alveolar lesions (MAL) in glands from wild-type mice and βERKO mice, but failed to induce MAL in mammary glands from αERKO mice. Microarray analysis of DMBA-treated mammary glands identified 28 functional pathways whose expression was significantly different in αERKO mice versus both βERKO and wild-type mice; key functions that were differentially expressed in αERKO mice included cell division, cell proliferation, and apoptosis. The data demonstrate distinct roles for ERα and ERβ in normal and neoplastic development in the mouse mammary gland, and suggest that EGF can mimic the ERα-mediated effects of E in this organ.
Project description:Introgressed variants from other species can be an important source of genetic variation because they may arise rapidly, can include multiple mutations on a single haplotype, and have often been pretested by selection in the species of origin. Although introgressed alleles are generally deleterious, several studies have reported introgression as the source of adaptive alleles-including the rodenticide-resistant variant of Vkorc1 that introgressed from Mus spretus into European populations of Mus musculus domesticus. Here, we conducted bidirectional genome scans to characterize introgressed regions into one wild population of M. spretus from Spain and three wild populations of M. m. domesticus from France, Germany, and Iran. Despite the fact that these species show considerable intrinsic postzygotic reproductive isolation, introgression was observed in all individuals, including in the M. musculus reference genome (GRCm38). Mus spretus individuals had a greater proportion of introgression compared with M. m. domesticus, and within M. m. domesticus, the proportion of introgression decreased with geographic distance from the area of sympatry. Introgression was observed on all autosomes for both species, but not on the X-chromosome in M. m. domesticus, consistent with known X-linked hybrid sterility and inviability genes that have been mapped to the M. spretus X-chromosome. Tract lengths were generally short with a few outliers of up to 2.7 Mb. Interestingly, the longest introgressed tracts were in olfactory receptor regions, and introgressed tracts were significantly enriched for olfactory receptor genes in both species, suggesting that introgression may be a source of functional novelty even between species with high barriers to gene flow.