TY - JOUR
T1 - Loss of caveolin-3 induces a lactogenic microenvironment that is protective against mammary tumor formation
AU - Sotgia, Federica
AU - Casimiro, Mathew C.
AU - Bonuccelli, Gloria
AU - Liu, Manran
AU - Whitaker-Menezes, Diana
AU - Er, Ozlem
AU - Daumer, Kristin M.
AU - Mercier, Isabelle
AU - Witkiewicz, Agnieszka K.
AU - Minetti, Carlo
AU - Capozza, Franco
AU - Gormley, Michael
AU - Quong, Andrew A.
AU - Rui, Hallgeir
AU - Frank, Philippe G.
AU - Milliman, Janet N.
AU - Knudsen, Erik S.
AU - Zhou, Jie
AU - Wang, Chenguang
AU - Pestell, Richard G.
AU - Lisanti, Michael P.
PY - 2009/2
Y1 - 2009/2
N2 - 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.
AB - 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.
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U2 - 10.2353/ajpath.2009.080653
DO - 10.2353/ajpath.2009.080653
M3 - Article
C2 - 19164602
AN - SCOPUS:59649087892
SN - 0002-9440
VL - 174
SP - 613
EP - 629
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 2
ER -