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Insulin-like Growth Factor-1 (IGF-1) Induces WISP-2/CCN5 via Multiple Molecular Cross-talks and Is Essential for Mitogenic Switch by IGF-1 Axis in Estrogen Receptor–Positive Breast Tumor Cells

¹ Cancer Research Unit, VA Medical Center, Kansas City, Missouri and ² Division of Hematology and Oncology, Department of Medicine and ³ Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas

Requests for reprints: Sushanta K. Banerjee, Cancer Research Unit, Research Division, 151, VA Medical Center, Kansas City, MO 64128. Phone: 816-861-4700 x 57057; Fax: 816-922-3320: E-mail: sbanerjee2{at}kumc.edu.

Previously, we have shown that the expression of Wnt-1–induced signaling protein-2 (WISP-2), also known as CCN5, can be regulated by multiple stimulants in estrogen receptor (ER)–positive breast tumor cells to exert their mitogenic action in these cells. Here, we show that insulin-like growth factor-1 (IGF-1), a strong mitogen, enhanced the expression of the WISP-2/CCN5 gene parallel with the induction of proliferation of ER-positive breast tumor cells. An additive effect was also seen in combination with estrogen. Perturbation of IGF-1–induced WISP-2/CCN5 expression by WISP-2–specific RNA interference impaired the mitogenic action of IGF-1 on ER-positive breast tumor cells. Furthermore, the studies have shown that the multiple molecular cross-talks and side-talks among IGF-1R, ER-, and phosphatidylinositol 3-kinase (PI3K)/Akt signaling molecules are required to induce WISP-2/CCN5 mRNA by IGF-1 in ER-positive, noninvasive breast tumor cells. Because a pure anti-ER ICI 182,780 is not only able to suppress the up-regulation of WISP-2/CCN5 mRNA expression by IGF-1, it also suppresses the PI3K/Akt activity induced by IGF-1 in MCF-7 cells; we anticipate that the membrane ER receptor may participate in this event. Collectively, these studies propose for the first time that WISP-2/CCN5 is an integral signaling molecule in mitogenic action of IGF-1 axis in ER-positive human breast tumor cells. [Cancer Res 2007;67(4):1520–6]

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