Loss of caveolin-3 induces a lactogenic microenvironment that is protective against mammary tumor formation

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

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

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 lobuloalveolar 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.

Original languageEnglish (US)
Pages (from-to)613-629
Number of pages17
JournalAmerican Journal of Pathology
Volume174
Issue number2
DOIs
StatePublished - Feb 2009

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Fingerprint Dive into the research topics of 'Loss of caveolin-3 induces a lactogenic microenvironment that is protective against mammary tumor formation'. Together they form a unique fingerprint.

  • Cite this

    Sotgia, F., Casimiro, M. C., Bonuccelli, G., Liu, M., Whitaker-Menezes, D., Er, O., Daumer, K. M., Mercier, I., Witkiewicz, A. K., Minetti, C., Capozza, F., Gormley, M., Quong, A. A., Rui, H., Frank, P. G., Milliman, J. N., Knudsen, E. S., Zhou, J., Wang, C., ... Lisanti, M. P. (2009). Loss of caveolin-3 induces a lactogenic microenvironment that is protective against mammary tumor formation. American Journal of Pathology, 174(2), 613-629. https://doi.org/10.2353/ajpath.2009.080653