Steroid receptor regulation of epidermal growth factor signaling through Src in breast and prostate cancer cells : Steroid antagonist action

• Published in: Cancer research (Chicago, Ill.) Ill.), 2005-11, Vol.65 (22), p.10585-10593
• Main Authors: MIGLIACCIO, Antimo, DI DOMENICO, Marina, CASTORIA, Gabriella, NANAYAKKARA, Merlin, LOMBARDI, Maria, DE FALCO, Antonietta, BILANCIO, Antonio, VARRICCHIO, Lilian, CIOCIOLA, Alessandra, AURICCHIO, Ferdinando
• Format: Article
• Language: English
• Subjects: Androgen Antagonists - pharmacology; Androgen Receptor Antagonists; Antineoplastic agents; Biological and medical sciences; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Line, Tumor; DNA, Neoplasm - biosynthesis; Epidermal Growth Factor - pharmacology; Estrogen Antagonists - pharmacology; Estrogen Receptor alpha - antagonists & inhibitors; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; Female; General aspects; Gynecology. Andrology. Obstetrics; Humans; Male; Mammary gland diseases; Medical sciences; Nephrology. Urinary tract diseases; Pharmacology. Drug treatments; Phosphorylation; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Receptor, Epidermal Growth Factor - metabolism; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; RNA, Small Interfering - genetics; Signal Transduction; src-Family Kinases - metabolism; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-05-0912

Under conditions of short-term hormone deprivation, epidermal growth factor (EGF) induces DNA synthesis, cytoskeletal changes, and Src activation in MCF-7 and LNCaP cells. These effects are drastically inhibited by pure estradiol or androgen antagonists, implicating a role of the steroid receptors in these findings. Interestingly, EGF triggers rapid association of Src with androgen receptor (AR) and estradiol receptor alpha (ERalpha) in MCF-7 cells or ERbeta in LNCaP cells. Here, we show that, through EGF receptor (EGFR) and erb-B2, EGF induces tyrosine phosphorylation of ER preassociated with AR, thereby triggering the assembly of ER/AR with Src and EGFR. Remarkably, experiments in Cos cells show that this complex stimulates EGF-triggered EGFR tyrosine phosphorylation. In turn, estradiol and androgen antagonists, through the Src-associated receptors, prevent Src activation by EGF and heavily reduce EGFR tyrosine phosphorylation and the subsequent multiple effects, including DNA synthesis and cytoskeletal changes in MCF-7 cells. In addition, knockdown of ERalpha or AR gene by small interfering RNA (siRNA) almost abolishes EGFR tyrosine phosphorylation and DNA synthesis in EGF-treated MCF-7 cells. The present findings reveal that steroid receptors have a key role in EGF signaling. EGFR tyrosine phosphorylation, depending on Src, is a part of this mechanism. Understanding of EGF-triggered growth and invasiveness of mammary and prostate cancer cells expressing steroid receptors is enhanced by this report, which reveals novel aspects of steroid receptor action.