Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 19, Pages 7820-7825Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1103441108
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Funding
- National Institutes of Health [R01 CA111482, N01 CN43309, RO1 CA136690, 1 S10 RR019291-01A2]
- National Center for Research Facilities [C06 RR14567]
- National Cancer Institute Cancer Center [1P30-CA-51008]
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Stem cell antigen (Sca)-1/Ly6A, a glycerophosphatidylinositol-linked surface protein, was found to be associated with murine stem cell-and progenitor cell-enriched populations, and also has been linked to the capacity of tumor-initiating cells. Despite these interesting associations, this protein's functional role in these processes remains largely unknown. To identify the mechanism underlying the protein's possible role in mammary tumorigenesis, Sca-1 expression was examined in Sca-1(+/EGFP) mice during carcinogenesis. Mammary tumor cells derived from these mice readily engrafted in syngeneic mice, and tumor growth was markedly inhibited on down-regulation of Sca-1 expression. The latter effect was associated with significantly elevated expression of the TGF-beta ligand growth differentiation factor-10 (GDF10), which was found to selectively activate TGF-beta receptor (T beta RI/II)-dependent Smad3 phosphorylation. Overexpression of GDF10 attenuated tumor formation; conversely, silencing of GDF10 expression reversed these effects. Sca-1 attenuated GDF10-dependent TGF-beta signaling by disrupting the heterodimerization of T beta RI and T beta RII receptors. These findings suggest a new functional role for Sca-1 in maintaining tumorigenicity, in part by acting as a potent suppressor of TGF-beta signaling.
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