title: Loss of caveolin-3 induces a lactogenic microenvironment that is protective against mammary tumor formation.
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.
authors.affiliation: Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA. federica.sotgia@jefferson.edu
authors.forename: Federica
authors.initials: F
authors.lastname: Sotgia
authors.forename: Mathew C
authors.initials: MC
authors.lastname: Casimiro
authors.forename: Gloria
authors.initials: G
authors.lastname: Bonuccelli
authors.forename: Manran
authors.initials: M
authors.lastname: Liu
authors.forename: Diana
authors.initials: D
authors.lastname: Whitaker-Menezes
authors.forename: Ozlem
authors.initials: O
authors.lastname: Er
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Daumer
authors.forename: Isabelle
authors.initials: I
authors.lastname: Mercier
authors.forename: Agnieszka K
authors.initials: AK
authors.lastname: Witkiewicz
authors.forename: Carlo
authors.initials: C
authors.lastname: Minetti
authors.forename: Franco
authors.initials: F
authors.lastname: Capozza
authors.forename: Michael
authors.initials: M
authors.lastname: Gormley
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Quong
authors.forename: Hallgeir
authors.initials: H
authors.lastname: Rui
authors.forename: Philippe G
authors.initials: PG
authors.lastname: Frank
authors.forename: Janet N
authors.initials: JN
authors.lastname: Milliman
authors.forename: Erik S
authors.initials: ES
authors.lastname: Knudsen
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.forename: Chenguang
authors.initials: C
authors.lastname: Wang
authors.forename: Richard G
authors.initials: RG
authors.lastname: Pestell
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
mesh_terms: D000818:Animals; D051244:Caveolin 3 / Q000235:genetics* / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007774:Lactation / Q000502:physiology*; D008297:Male; D008321:Mammary Glands, Animal / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D008895:Milk, Human / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011247:Pregnancy
chemical_list: D051244:Caveolin 3