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PMID: 19164602 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

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

The American journal of pathology ·Vol. 174 ·No. 2 ·2009-02-00 ·Pages 613-29

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

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.

MeSH Terms
Animals Caveolin 3/genetics,metabolism Cell Movement/physiology Female Gene Expression Gene Expression Profiling Humans Immunohistochemistry In Situ Nick-End Labeling Lactation/physiology Male Mammary Glands, Animal/metabolism Mammary Neoplasms, Experimental/genetics,metabolism Mice Mice, Mutant Strains Milk, Human/metabolism Oligonucleotide Array Sequence Analysis Phenotype Polymerase Chain Reaction Pregnancy
Chemicals
Caveolin 3
Authors & Affiliations
21 authors, click to expand affiliations / ORCID
Sotgia Federica
Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA. federica.sotgia@jefferson.edu
Casimiro Mathew C
Bonuccelli Gloria
Liu Manran
Whitaker-Menezes Diana
Er Ozlem
Daumer Kristin M
Mercier Isabelle
Witkiewicz Agnieszka K
Minetti Carlo
Capozza Franco
Gormley Michael
Quong Andrew A
Rui Hallgeir
Frank Philippe G
Milliman Janet N
Knudsen Erik S
Zhou Jie
Wang Chenguang
Pestell Richard G
Lisanti Michael P
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Article Info
Journal
The American journal of pathology
Abbr.
Am J Pathol
ISSN
1525-2191
DOI
10.2353/ajpath.2009.080653
Email
federica.sotgia@jefferson.edu
Published
2009-02-00
Pages
613-29
Language
English
Region
United States
NLM ID
0370502
PMCID
PMC2630569
Subset
IM
Grants
NCI NIH HHS · R01 CA075503 · United States
NCI NIH HHS · R01 CA098779 · United States
NCI NIH HHS · R01-CA-120876 · United States
NCI NIH HHS · R01 CA120876 · United States
NCI NIH HHS · R01-CA-70896 · United States
NCI NIH HHS · R01-CA-098779 · United States
NCI NIH HHS · R01-CA-86072 · United States
NCI NIH HHS · R01 CA070896 · United States
NCI NIH HHS · R01-CA-75503 · United States
NCI NIH HHS · R01 CA107382 · United States
NCI NIH HHS · P30 CA056036 · United States
NCI NIH HHS · R01-CA-80250 · United States
NCI NIH HHS · P30-CA-56036 · United States
NCI NIH HHS · R01-CA-107382 · United States
NCI NIH HHS · R01 CA080250 · United States
NCI NIH HHS · R01 CA086072 · United States
External Links
PubMed source DOI: 10.2353/ajpath.2009.080653 PMC Full Text View journal details
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