ArrayExpress Uploader05481arrayexpress_sid6Here, we show that functional loss of a single gene is sufficient to confer constitutive milk protein production and protection against...19164602E-GEOD-12881/profile/8773/arrayexpressuploader06breastcancercellgenomeglandlinemammary tumormilkmuscleproteinDec.12, 2014Falsetranscription-profiling-of-mouse-wt-and-cav-3-knocE-GEOD-12881_A-AFFY-45Transcription profiling of mouse WT and Cav-3 knockouts on FVB/N genetic background mammary glands reveals loss of caveolin-3 induces the development of a lactogenic microenvironmentNov.10, 2014Here, we show that functional loss of a single gene is sufficient to confer constitutive milk protein production and protection against mammary tumor formation. Caveolin-3 (Cav-3), a muscle-specific caveolin-related gene, is highly expressed in striated and smooth muscle cells. We demonstrate that Cav-3 is also expressed in myoepithelial cells within the mammary gland. To determine if genetic ablation of Cav-3 expression affects adult mammary gland development, we next studied the phenotype(s) of Cav-3 (-/-) null mice. Interestingly, detailed analysis of Cav-3 (-/-) virgin mammary glands shows dramatic increases in ductal thickness, side-branching, and the development of extensive lobulo-alveolar hyperplasia, akin to the changes normally observed during pregnancy and lactation. Analysis by genome-wide expression profiling reveals the upregulation of gene transcripts associated with pregnancy/lactation, mammary stem cells, and human breast cancers, consistent with a constitutive lactogenic phenotype. The expression levels of three key transcriptional regulators of lactation, namely Elf5, Stat5a, and c-Myc are also significantly elevated. Experiments with pregnant mice directly show that Cav-3 (-/-) mice undergo precocious lactation. Finally, using orthotopic implantation of a transformed mammary cell line (known as Met-1), we demonstrate that virgin Cav-3 (-/-) mice are dramatically protected against mammary tumor formation. Interestingly, Cav-3 (+/-) mice also show similar protection, indicating that even reductions in Cav-3 levels are sufficient to render these mice resistant to tumorigenesis. Thus, Cav-3 (-/-) mice are a novel preclinical model to study the protective effects of a constitutive lactogenic microenviroment on mammary tumor onset and progression. Our current studies have broad implications for using the lactogenic micro-environment as a paradigm to discover new therapies for the prevention and/or treatment of human breast cancers. Most importantly, a lactation-based therapeutic strategy would provide a more natural and nontoxic approach to the development of novel anti-cancer therapies. Experiment Overall Design: All WT and Cav-3 knockout (KO) mice used in this study were in the FVB/N genetic background. 4-month old virgin female mice were utilized in a micro array study between 3 wildtype and 3 Caveolin-3 knock-out mammary glands.http://www.ebi.ac.uk/arrayexpress/experiments/E-GEOD-12881mousehttp://www.ebi.ac.uk/arrayexpress/experiments/E-GEOD-12881/samples/