Abstract 520: Characterizing the AC1-exemestane resistant cell line to reveal the underlying mechanism of resistance to aromatase inhibitors in estrogen-dependent breast cancer .

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Estrogen receptor positive (ER+) breast cancer depends on the hormone estrogen for growth and is one of the most common forms of breast cancer present among postmenopausal women. One type of therapy that has proven highly effective in treating this type of breast cancer is aromatase inhibitors. Aromatase is an enzyme that mediates the conversion of androgens (i.e. androstenedione) into estrogens. Aromatase inhibitors (AIs) letrozole, anastrazole, and exemestane, are used to treat estrogen receptor positive (ER+) patients by reducing the levels of estrogen produced via the Aromatase enzyme. Though AIs are dynamically effective at treating ER+ cancers, a significant amount of breast cancer patients become resistant to these drugs over time. The purpose of this study is to gain a better understanding of acquired AI resistance by 1) developing a breast cancer cell line (AC1-ExR) that mimics clinical acquired exemestane resistance; and 2) characterizing this cell line. The novel cell line was extracted from ER+ tumors of xenograft mouse models. The xenograft tumors initially regressed, but after long-term treatment, they became resistant to exemestane, a type of AI, and began to grow. We characterized the AC1-ExR cell line by analyzing their drug sensitivity. Aromatase Assays were performed to measure the aromatase activity in these cells following treatment with 10−6 M of exemestane. The aromatase activity in the AC1-ExR cell line, when treated with exemestane, was less than that of the AC1 parental cell line: average aromatase activity of 31.1 fmol/mg protein*hr compared to average aromatase activity of 72.1 fmol/mg protein*hr in the parental cell line. In addition, AC1-ExR cells exhibited more cancer stem cell-like properties than the AC1 cells. The average mammosphere count for AC1-ExR and AC1 cells was 54 and 33.3 mammospheres, respectively. In the ER+ pathway, interactions between several growth factor signaling pathways have shown to increase hypersensitivity of the ER-alpha receptor to estrogen stimuli. Specifically, inhibitors to the insulin-like growth factor receptor (IGF-1R) have shown to significantly suppress the growth of breast cancer cells in vitro. Identification of growth factor signaling pathways that may be relevant to the ER+ pathway and crosstalk between ER-alpha and IGF-1R, EGFR, and/or other active receptors may reveal their potential role in aromatase resistance in ACI-ExR cells. Characterization of the AC1-ExR cell line has revealed decrease in aromatase activity. A comprehensive understanding of this mechanism may serve as a means of treatment in patients with ER+ positive breast cancer. This work was funded in part by NIH/NIGMS MARC U*STAR T34 08663 National Research Service Award to UMBC and an RO1 CA-62483 Grant by the National Cancer Institute of the National Institutes of Health Citation Format: Joyce C. Ohiri, Armina Kazi, Amanda Schech, Angela M. Brodie. Characterizing the AC1-exemestane resistant cell line to reveal the underlying mechanism of resistance to aromatase inhibitors in estrogen-dependent breast 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 520. doi:10.1158/1538-7445.AM2013-520