17Beta-Estradiol Promotes Aggressive Laryngeal Cancer Through Membrane-Associated Estrogen Receptor-Alpha 36

• Type of Material: Article
• Authors: Nofrat Schwartz, Meir Hospital; Reyhaan A Chaudhri, Georgia Institute of Technology; Agreen Hadadi, Georgia Institute of Technology; Zvi Schwartz, University of Texas Health Science Center at San Antonio; Barbara Boyan, Emory University
• Language: English
• Date: 2014-02-01
• Publisher: Springer
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2013, Springer Science Business Media New York
• Final Published Version (URL): http://dx.doi.org/10.1007/s12672-013-0161-y
• Title of Journal or Parent Work: Hormones and Cancer
• Volume: 5
• Issue: 1
• Start Page: 22
• End Page: 32
• Grant/Funding Information: National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR000454 and TL1TR000456; Price Gilbert, Jr. Foundation
• Keywords: GROWTH; Endocrinology & Metabolism; PROTEIN-KINASE-C; Oncology; Life Sciences & Biomedicine; BREAST-CANCER; Science & Technology; VARIANT; ESTRADIOL; TAMOXIFEN; EXPRESSION; CELLS; RECEPTOR-ALPHA-36; ACTIVATION

Abstract

17β-estradiol (E2) plays a key role in tumorigenesis by enhancing cell survivability and metastasis through its cytoplasmic receptors. Recently, a variant of estrogen receptor alpha, ERα36 has been implicated as a substantial mediator of E2's proliferative and antiapoptotic effects through rapid membrane-associated signaling, and cancers previously regarded as hormone-independent due to the absence of traditional receptors, may in fact be susceptible to E2. Despite rising from a secondary sex organ and having a clear gender disposition, laryngeal cancer is not uniformly accepted as hormone dependent, even in the face of compelling evidence of E2 responsiveness. The aim of this study was to further elucidate the role of E2 in the tumorigenesis of laryngeal cancer, both in vitro and in vivo. ERα36 presence was evaluated in membranes of the laryngeal carcinoma cell line, Hep2, as well as in laryngeal tumor samples. In vitro ERα36 was found to mediate rapid activation of protein kinase C and phospholipase D by E2, leading to increased proliferation and protection against chemotherapy-induced apoptosis. Furthermore, in response to E2 activation of ERα36, an upregulation of angiogenic and metastatic factors was observed. Clinical analysis of laryngeal tumors revealed a similar association between the amount of ERα36 and VEGF and indicated a role in lymph node metastasis. These findings present compelling evidence of ERα36-dependent E2 signaling in laryngeal cancer. Thus, targeting ERα36 may reduce the deleterious effects of E2 in laryngeal cancer, ultimately suggesting the importance of antiestrogen therapy or the production of novel drugs that specifically target ERα36. © 2013 Springer Science+Business Media New York.