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17ß-Estradiol Up-regulates the Insulin-like Growth Factor Receptor through a Nongenotropic Pathway in Prostate Cancer Cells

¹ Endocrinologia, Dipartimento di Medicina Interna e Medicina Specialistica, University of Catania, Ospedale Garibaldi-Nesima, Catania, Italy and ² Endocrinologia, Dipartimento di Medicina Sperimentale e Clinica, University of Catanzaro, Catanzaro, Italy

Requests for reprints: Riccardo Vigneri, Endocrinologia, Dipartimento di Medicina Interna e Medicina Specialistica, University of Catania, Ospedale Garibaldi-Nesima, via Palermo 632, 95122 Catania, Italy. Phone: 39-095-759-8702; Fax: 39-095-715-8072; E-mail: vigneri{at}unict.it.

Prostate carcinomas frequently express estrogen receptors (ER), irrespective of androgen receptor (AR) expression; however, the role of ERs and estrogens in prostate cancer is controversial. We found that 17ß-estradiol (E₂) is able to markedly up-regulate insulin-like growth factor (IGF)-I receptor (IGF-IR) mRNA and protein expression in both AR-positive (LNCaP cells) and AR-negative (PC-3 cells) prostate cancer cells. This effect occurs not only via ER but also via ERß stimulation and is specific for IGF-IR because it does not involve the cognate insulin receptor. IGF-IR up-regulation is associated with increased IGF-IR phosphorylation and with increased mitogenic and motogenic activities in response to IGF-I. IGF-IR up-regulation by E₂ does not require ER binding to DNA and is poorly sensitive to antiestrogen blockade, whereas it is associated with the activation of cytosolic kinase cascades involving Src, extracellular signal–regulated kinase (ERK)-1/2, and, to a lesser extent, phosphatidylinositol 3-kinase and is sensitive to the inhibition of these kinases. In conclusion, our data indicate that estrogens may contribute to IGF system deregulation in prostate cancer through the activation of a nongenotropic pathway. Estrogens may have a role, therefore, in tumor progression to androgen independence. Inhibition of the IGF-IR or the Src-ERK pathway should be considered, therefore, as an adjuvant therapy in prostate cancer. [Cancer Res 2007;67(18):8932–41]

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				Correction: 17{beta}-Estradiol Up-regulates IGF-IR in Prostate Cancer Cancer Res., November 1, 2007; 67(21): 10623 - 10623. [Full Text] [PDF]