title: Steroid receptor regulation of epidermal growth factor signaling through Src in breast and prostate cancer cells: steroid antagonist action.
abstract: 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.
authors.affiliation: Dipartimento di Patologia Generale, Facoltà di Medicina e Chirurgia, II Università di Napoli, Naples, Italy.
authors.forename: Antimo
authors.initials: A
authors.lastname: Migliaccio
authors.forename: Marina
authors.initials: M
authors.lastname: Di Domenico
authors.forename: Gabriella
authors.initials: G
authors.lastname: Castoria
authors.forename: Merlin
authors.initials: M
authors.lastname: Nanayakkara
authors.forename: Maria
authors.initials: M
authors.lastname: Lombardi
authors.forename: Antonietta
authors.initials: A
authors.lastname: de Falco
authors.forename: Antonio
authors.initials: A
authors.lastname: Bilancio
authors.forename: Lilian
authors.initials: L
authors.lastname: Varricchio
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ciociola
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Auricchio
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology*; D059002:Androgen Receptor Antagonists; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000378:metabolism*; D004965:Estrogen Antagonists / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D004273:DNA, Neoplasm; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D019061:src-Family Kinases