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(American Journal of Pathology. 2009;174:613-629.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080653

Loss of Caveolin-3 Induces a Lactogenic Microenvironment that Is Protective Against Mammary Tumor Formation

Federica Sotgia*{dagger}{ddagger}, Mathew C. Casimiro*{dagger}, Gloria Bonuccelli*{dagger}, Manran Liu*{dagger}, Diana Whitaker-Menezes*{dagger}, Ozlem Er*{dagger}, Kristin M. Daumer*{dagger}, Isabelle Mercier*{dagger}, Agnieszka K. Witkiewicz§, Carlo Minetti{ddagger}, Franco Capozza*{dagger}, Michael Gormley*{dagger}, Andrew A. Quong*{dagger}, Hallgeir Rui*{dagger}, Philippe G. Frank*{dagger}, Janet N. Milliman*{dagger}, Erik S. Knudsen*{dagger}, Jie Zhou*{dagger}, Chenguang Wang*{dagger}, Richard G. Pestell*{dagger} and Michael P. Lisanti*{dagger}{ddagger}

From the Departments of Cancer Biology and Medical Oncology,* Kimmel Cancer Center, the Stem Cell Biology and Regenerative Medicine Center,{dagger} and the Department of Pathology, Anatomy, and Cell Biology,§ Thomas Jefferson University, Philadelphia, Pennsylvania; and the Muscular and Neurodegenerative Disease Unit,{ddagger} University of Genoa and G. Gaslini Pediatric Institute, Genoa, Italy

Here, 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 muscle cells. We demonstrate that Cav-3 is also expressed in myoepithelial cells within the mammary gland. To determine whether genetic ablation of Cav-3 expression affects adult mammary gland development, we studied the phenotype(s) of Cav-3–/–-null mice. Interestingly, Cav-3–/– virgin mammary glands developed lobulo-alveolar hyperplasia, akin to the changes normally observed during pregnancy and lactation. Genome-wide expression profiling revealed up-regulation of gene transcripts associated with pregnancy/lactation, mammary stem cells, and human breast cancers, consistent with a constitutive lactogenic phenotype. Expression levels of three key transcriptional regulators of lactation, namely Elf5, Stat5a, and c-Myc, were also significantly elevated. Experiments with pregnant mice directly showed that Cav-3–/– mice underwent precocious lactation. Finally, using orthotopic tumor cell implantation, we demonstrated that virgin Cav-3–/– mice were dramatically protected against mammary tumor formation. Thus, Cav-3–/– mice are a novel preclinical model to study the protective effects of a lactogenic microenvironment on mammary tumor onset and progression. Our current studies have broad implications for using the lactogenic microenvironment as a paradigm to discover new therapies for the prevention and/or treatment of human breast cancers.


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