Caveolin-1-deficient mice have an increased mammary stem cell population with upregulation of Wnt/beta-catenin signaling.
Here, we show that a caveolin-1 (Cav-1) deficiency leads to an amplification of the adult mammary stem cell population, both in vivo and in vitro. First, the expression of two stem cell markers, Sca-1 and Keratin 6, is dramatically increased in the hyperplastic mammary ducts of Cav-1 deficient mice, suggesting that loss of Cav-1 induces the accumulation of a progenitor cell population in the mammary gland. To independently validate these results, we reconstituted mammary acini formation in vitro via a 3D Matrigel assay system--using primary cultures of mammary epithelial cells derived from WT and Cav-1 deficient mice. We show that Cav-1 null 3D epithelial structures display an intense increase in the expression of three stem cell markers, i.e., Sca-1, keratin 6 and keratin 5. Overall, we observed a 2-to-3 fold increase in the number of Cav-1 KO acini that are positive for a given stem cell marker. Also, we show that such amplification of progenitor cells has functional consequences, as demonstrated by the abnormal presence of myoepithelial cells in the hyperplastic lesions of Cav-1 deficient mammary glands. Finally, we provide evidence that hyper-activation of Wnt/beta-catenin signaling may constitute one of the down-stream mechanisms leading to mammary stem cell accumulation. The longevity and slow-dividing properties of mammary stem cells facilitates the accumulation of genetic alterations, and renders these progenitor cells the likely precursors of malignant derivatives. As such, we propose that loss of Cav-1 induces the accumulation of mammary stem cells, and that this event may be an initiating factor during mammary tumorigenesis.
Sotgia
Federica
F
Department of Molecular Pharmacology & Medicine, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Williams
Terence M
TM
Cohen
Alex W
AW
Minetti
Carlo
C
Pestell
Richard G
RG
Lisanti
Michael P
MP
D000818:Animals; D000067696:Ataxin-1; D000067528:Ataxins; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051242:Caveolin 1 / Q000172:deficiency* / Q000378:metabolism; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology; D007633:Keratins / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism*; D051820:TCF Transcription Factors / Q000378:metabolism; D000073940:Transcription Factor 4; D015854:Up-Regulation / Q000235:genetics*; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
D000067696:Ataxin-1; D000067528:Ataxins; C000593750:Atxn1 protein, mouse; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C495541:Cav1 protein, mouse; D051242:Caveolin 1; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D051820:TCF Transcription Factors; C090743:Tcf4 protein, mouse; D000073940:Transcription Factor 4; D051153:Wnt Proteins; D051176:beta Catenin; D007633:Keratins