17β-estradiol up-regulates the insulin-like growth factor receptor through a nongenotropic pathway in prostate cancer cells

• Published in: Cancer research (Chicago, Ill.) Ill.), 2007-09, Vol.67 (18), p.8932-8941
• Main Authors: PANDINI, Giuseppe, GENUA, Marco, FRASCA, Francesco, SQUATRITO, Sebastiano, VIGNERI, Riccardo, BELFIORE, Antonino
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Biological and medical sciences; Gynecology. Andrology. Obstetrics; Male genital diseases; Medical sciences; Nephrology. Urinary tract diseases; Pharmacology. Drug treatments; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-06-4814

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 17β-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 ERα but also via ERβ 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]