Abstract
Abstract Tamoxifen, a selective estrogen receptor modulator (SERM), is used as a first line treatment for estrogen receptor (ER) positive breast cancer. Though most ER-positive breast cancers initially respond to tamoxifen, the development of resistance impedes durable responses to this intervention. Further, predicting which tumors are most likely to develop resistance remains a challenge. In part, this is due to the complexity of the mechanisms underlying resistance and the difficulty in translating insights from studies of tamoxifen pharmacology in vitro to the clinical setting. However, the results of most studies support the idea that resistance represents a change that enables cells to recognize tamoxifen as an agonist instead of an antagonist. Thus, identifying biomarkers downstream of the ER pathway that read on the relative agonist/antagonist activity of tamoxifen would likely improve the clinical utility of tamoxifen and other endocrine therapies in breast cancer. Recent work by our lab and other groups has identified AGR2 as an ER target gene whose expression is induced by both 17β-estradiol (E2) and 4-hydroxytamoxifen (4OHT). AGR2 is a proto-oncogene whose elevated expression is associated with increased cell proliferation, migration and invasion in breast cancer. Additionally, in the clinical setting, AGR2 has been identified as playing an important role in tamoxifen resistance. In a cell line established within our lab from a human xenograft model of tamoxifen resistance (TamR), AGR2 is significantly overexpressed compared to the parental MCF7 cell line. Knockdown of AGR2 expression in the TamR cell line resulted in a dramatic inhibition of E2 induced cell growth and migratory potential, attesting to its importance in the pathobiology of advanced cancers. When overexpressed in the MCF7 cell line, AGR2 was secreted and induced migratory potential in the MCF7 and TamR breast cancer cell lines in vitro. Additionally, overexpressed AGR2 significantly increased tumor growth in vivo. In both the MCF7 and TamR cellular models of breast cancer, AGR2 expression is required for ER expression. However, in the TamR cell line, AGR2 expression is no longer controlled by ER, suggesting that under selective pressure, the TamR cell line has acquired an alternative mechanism to upregulate AGR2 expression. Additional work is currently underway to further understand the mechanism of AGR2 regulation as breast cancers progress to a tamoxifen resistant state. This work is supported by a DOD Breast Cancer Postdoctoral Fellowship BC103843 (TMW) and a National Institutes of Health Grant R37 DK048807 (DPM). Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A96. Citation Format: Tricia M. Wright, Suzanne E. Wardell, Erik R. Nelson, Donald P. McDonnell. The role of the proto-oncogene AGR2 in endocrine resistant breast cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A96.
Published Version
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