Loss of caveolin-3 induces a lactogenic microenvironment that is protective against mammary tumor formation.
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.
Sotgia
Federica
F
Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA. federica.sotgia@jefferson.edu
Casimiro
Mathew C
MC
Bonuccelli
Gloria
G
Liu
Manran
M
Whitaker-Menezes
Diana
D
Er
Ozlem
O
Daumer
Kristin M
KM
Mercier
Isabelle
I
Witkiewicz
Agnieszka K
AK
Minetti
Carlo
C
Capozza
Franco
F
Gormley
Michael
M
Quong
Andrew A
AA
Rui
Hallgeir
H
Frank
Philippe G
PG
Milliman
Janet N
JN
Knudsen
Erik S
ES
Zhou
Jie
J
Wang
Chenguang
C
Pestell
Richard G
RG
Lisanti
Michael P
MP
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
D051244:Caveolin 3