Abstract Metabotropic glutamate receptor 1 (GRM1), first recognized as an important factor in the central nervous system, has more recently been implicated in melanomagenesis and breast cancer pathogenesis. Oncogenic mediators of GRM1-associated effects include both MAPK and AKT signaling cascades. Modulation of GRM1 activity in melanoma and estrogen receptor negative (ER-) breast cancer cells inhibits anchorage independent growth, migration, proliferation, and/or downstream activation of Akt and ERK. Data from our laboratory show that a significantly higher fraction of breast tumors express GRM1 compared to normal breast tissue, and GRM1 expression is more highly correlated with ER positivity. Moreover, higher GRM1 expression in human ER+ breast cancers treated with the anti-estrogen tamoxifen associates with a shorter distant metastasis free survival as compared to low expressors further supporting a critical role in ER+ breast cancer. We hypothesize that ER has both genomic and non-genomic effects on GRM1. We evaluated the effect of hormonal treatment on GRM1 protein expression in ER+ MCF7 and ER- MDA-MB-231 breast cancer cells. Estradiol increases GRM1 expression, and this effect is abrogated by the anti-estrogen tamoxifen in MCF7 but not in MDA-MB-231 cells. These genomic effects may be exerted through three putative ER binding sites within the GRM1 promoter. We have confirmed that ER binds to one of these sites by chromatin immunoprecipitation, further supported by ChiPSeq data. GRM1 promoter activity is increased by estradiol treatment using a luciferase reporter assay validating transcriptional activation by ER. To support a non-genomic role for ER with GRM1, we have shown that ER physically interacts with GRM1 in breast cancer cells by in vitro proximity ligation assay and by co-immunoprecipitation in immortalized mouse mammary epithelial cells (iMMECs) stably expressing GRM1. Stable introduction of GRM1 into iMMECs, which lack endogenous GRM1, reduces sensitivity to tamoxifen as compared to control iMMECs. In MCF7 cells, the combination of tamoxifen with GRM1 modulators riluzole or BAY 36-7620 produces synergistic effects. As estradiol activates MAPK signaling in breast cancer cells, we hypothesize that this may be mediated by both the physical interaction of GRM1 and ER and the indirect effects on GRM1 transcription. Results of these studies suggest that GRM1 may be a valuable therapeutic target in ER+ breast tumors. Citation Format: Sonia C. Dolfi, Madhura S. Mehta, David Kornblum, Andrew Boughton, Hussein Rahim, Daniel Medina, Kim M. Hirshfield. Regulation of GRM1 by estrogen receptor in breast cancer. [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 4457. doi:10.1158/1538-7445.AM2014-4457