Faculty Collaboration Database

Loss of caveolin-3 induces a lactogenic microenvironment that is protective against mammary tumor formation. Am J Pathol 2009 Feb;174(2):613-29

Date

01/24/2009

Pubmed ID

19164602

Pubmed Central ID

PMC2630569

DOI

10.2353/ajpath.2009.080653

Scopus ID

2-s2.0-59649087892 (requires institutional sign-in at Scopus site)   17 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 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.

Author List

Sotgia F, Casimiro MC, Bonuccelli G, Liu M, Whitaker-Menezes D, Er O, Daumer KM, Mercier I, Witkiewicz AK, Minetti C, Capozza F, Gormley M, Quong AA, Rui H, Frank PG, Milliman JN, Knudsen ES, Zhou J, Wang C, Pestell RG, Lisanti MP

MESH terms used to index this publication - Major topics in bold

Animals
Caveolin 3
Cell Movement
Female
Gene Expression
Gene Expression Profiling
Humans
Immunohistochemistry
In Situ Nick-End Labeling
Lactation
Male
Mammary Glands, Animal
Mammary Neoplasms, Experimental
Mice
Mice, Mutant Strains
Milk, Human
Oligonucleotide Array Sequence Analysis
Phenotype
Polymerase Chain Reaction
Pregnancy