Stem cell antigen-1 enhances tumorigenicity by disruption of growth differentiation factor-10 (GDF10)-dependent TGF-β signaling

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 19; pp. 7820 - 7825
• Main Authors: Upadhyay, Geeta, Yin, Yuzhi, Yuan, Hongyan, Li, Xin, Derynck, Rik, Glazer, Robert I., Brugge, Joan S.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 10-05-2011; National Acad Sciences
• Subjects: Animals; Antigens, Ly - genetics; Antigens, Ly - metabolism; Base Sequence; Biological Sciences; Cancer; Cell growth; Cell lines; Female; Gene expression regulation; Gene Expression Regulation, Neoplastic; Green Fluorescent Proteins - genetics; Growth Differentiation Factor 10 - genetics; Growth Differentiation Factor 10 - metabolism; Ligands; Mammary glands; Mammary Neoplasms, Experimental - etiology; Mammary Neoplasms, Experimental - genetics; Mammary Neoplasms, Experimental - metabolism; Membrane Proteins - genetics; Membrane Proteins - metabolism; Messenger RNA; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Models, Biological; Protein-Serine-Threonine Kinases - deficiency; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Receptors; Receptors, Transforming Growth Factor beta - deficiency; Receptors, Transforming Growth Factor beta - genetics; Receptors, Transforming Growth Factor beta - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA, Neoplasm - genetics; RNA, Neoplasm - metabolism; Signal Transduction; Smad3 Protein - metabolism; Stem cells; Transforming Growth Factor beta - metabolism; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1103441108

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-β ligand growth differentiation factor-10 (GDF10), which was found to selectively activate TGF-β receptor (TβRI/II)-dependent Smad3 phosphorylation. Overexpression of GDF10 attenuated tumor formation; conversely, silencing of GDF10 expression reversed these effects. Sca-1 attenuated GDF10-dependent TGF-β signaling by disrupting the heterodimerization of TßRI and TßRIl receptors. These findings suggest a new functional role for Sca-1 in maintaining tumorigenicity, in part by acting as a potent suppressor of TGF-β signaling.