Abstract 1048: Targeted BRAF therapy attenuates the promotional activity of estrogen in thyroid cancer.

Abstract

Abstract Thyroid cancer, which is three to four times more prevalent in women than men, is the most common endocrine-related cancer in the United States and its incidence has increased in the past three decades. Among various genetic lesions identified in thyroid cancer, the BRAF V600E mutation is found in 50% of papillary thyroid cancers and affords an opportunity for targeted drug therapy. Our laboratory identified estrogen as a promotional factor in thyroid cancer, as estrogen enhances proliferation, migration, and invasion of thyroid cancer cells in vitro. Since the mitotic activity of estrogen is partially mediated by the mitogen-activated protein kinase (MAPK) pathway, we hypothesized that a targeted BRAF V600E inhibitor, PLX4032, would inhibit estrogen-mediated tumor-promoting activity. Results demonstrate that PLX4032 abrogates estrogen-induced increases in proliferation and invasion of BRAF V600E-mutated BCPAP papillary thyroid cancer cells in a dose-dependent manner. In contrast, this phenomenon was not observed in Nthy-ori 3-1 thyroid cells, which are wild-type immortalized thyroid cells without the BRAF V600E mutation. Expression of estrogen receptor is not modulated by PLX4032 treatment, indicating that PLX4032 targets signal transduction pathways in estrogen-responsive thyroid cells. PLX4032 down-regulates the expression of key signaling molecules of the BRAF pathway, including mitogen-activated protein kinase kinase (p-MEK), extracellular-signal regulated kinases (p-ERK), and mammalian target of rapamycin (p-mTOR) in BRAF-mutated BCPAP cells and does not alter the expression of these signaling molecules in wild-type Nthy-ori 3-1 cells. These results demonstrate a direct interlinking of a genetic lesion amenable to drug therapy with the promotional activity of estrogen. These findings will lead to an evaluation of combinational therapy including anti-estrogens and PLX4032 in preclinical animal models and a subset of patients harboring the BRAF V600E mutation. Targeting growth-promoting signal transduction pathways constitutively activated by genetic lesions will ultimately aid in overcoming resistance to traditional radioactive iodine therapy in patients with specific mutations such as BRAF V600E. Citation Format: Elyse K. Hanly, Shilpi Rajoria, Andrea L. George, Robert Suriano, Jan Geliebter, Harry Pantelides, Edward J. Shin, Raj K. Tiwari. Targeted BRAF therapy attenuates the promotional activity of estrogen in thyroid cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1048. doi:10.1158/1538-7445.AM2013-1048