Project description:P190B RhoGAP is required for mammary gland development, and its overexpression disrupts mammary gland branching morphogenesis. To better understand the mechanisms by which p190B regulates mammary gland development we performed gene expression microarray analysis on mammary epithelial cells isolated from p190B overexpressing transgenic mice compared to control mice.
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:Variant analysis from whole exome sequencing (WES), performed on primary tumorigenic cells obtained from (1) a GEMM of metastatic TNBC mice model overexpressing both human Prune-1 and Wnt1 under the control of Mouse Mammary Tumor Virus MMTV promoter in mammary gland (i.e., MMTV-Prune-1/Wnt1); (2) a GEMM of TNBC mice model overexpressing Wnt1 under the control of MMTV promoter in mammary gland (i.e., MMTV-Wnt1).
Project description:We collected whole genome testis expression data from hybrid zone mice. We integrated GWAS mapping of testis expression traits and low testis weight to gain insight into the genetic basis of hybrid male sterility.
Project description:P190B RhoGAP is required for mammary gland development, and its overexpression disrupts mammary gland branching morphogenesis. To better understand the mechanisms by which p190B regulates mammary gland development we performed gene expression microarray analysis on mammary epithelial cells isolated from p190B overexpressing transgenic mice compared to control mice. The mice used in this study were previously developed to inducibly overexpress p190B selectively in the mammary gland (Vargo-Gogola 2006). FVB/N mice carrying the MMTV-rtTA and TetO-p190B-IRES-luciferase transgenes or the MMTV-rtTA transgene only (Gunther EJ, FASEB) were fed doxycycline (Dox) chow (2 g/kg) for 7 d prior to removal of mammary glands and isolation of primary mammary epithelial cells at 6 weeks of age.
