Abstract 2122: Androgen decreases proliferation of thyroid cancer cells

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA The incidence of thyroid cancer in the United States has significantly increased over the past decade, with over 60,220 cases predicted for 2013. While premenopausal women have an approximately four fold higher incidence of papillary thyroid cancer (PTC) than men, once diagnosed, PTC in men exhibits increased aggressiveness and results in poorer clinical outcomes. These paradoxical observations led us to investigate the role that androgens and/or androgen receptors play in PTC. Analysis of AR expression in 24 PTC patient tissue samples indicated a 5.97 fold reduction in AR expression compared to matched, normal tissue (P<0.0001). To more fully investigate the function of androgen/AR in thyroid cells in a more controlled experimental system, the AR cDNA (pSG5-AR) was subcloned into the pcDNA3.1+ expression vector and stably transfected into 8505C anaplastic/PTC cells. Addition of DHT to the 8505C-transfected clone, 84E7, resulted in AR translocation into the nucleus and a 48% reduction in proliferation (p=0.01) at 72 hours, as well as a shift in the cell cycle toward G1 arrest during the same time period. Transcription profiling using RNA-Seq and gene ontology analysis revealed significant changes in the process of cell proliferation (p=2.47e-24) possibly due to significant changes in CDK1A/p21 (up 3.42 fold), RhoB (up 50 fold), Jun (down 1.7 fold), SCF (down 3.31 fold) and NFKBIA (up 2.36). Additionally, expression levels of other cell cycle proteins, including CDK6 and multiple MCMs were also significantly reduced when AR was activated by DHT. FKBP5, the immunophilin which negatively regulates proliferation and is thought to play various roles in the neoplastic process, was up-regulated by androgen ∼8 fold and ∼4 fold on the mRNA and protein levels, respectively. Collectively, these data provide a molecular basis for the decreased proliferation noted. Further, these data suggest that the expression of androgen/AR in thyroid cells plays a protective, anti-proliferative role in normal thyroid tissue that is lost in neoplastic transformation resulting in dysregulation of cell cycle genes normally under negative AR control. The expression levels of AR, as well as available androgens, may play a role in the etiology of PTC, the differential incidence of the disease, as well as the different clinical presentations and outcomes between women and men. Citation Format: Melanie Elizabeth MacEwan, Timmy O'Connell, Hong Zhao, Codrin Iacob, Nina Suslina, Augustine Moscatello, Edward Shin, Raj Tiwari, Zbigniew Darzynkiewicz, Jan Geliebter. Androgen decreases proliferation of thyroid cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2122. doi:10.1158/1538-7445.AM2014-2122