Abstract Despite epidemiologic studies suggesting a link between melanoma and breast cancer, molecular mechanisms leading to these associations have not been elucidated. Overexpression of metabotropic glutamate receptor 1 (GRM1) has been implicated in melanomagenesis. Its primary action occurs through activation of the MAPK signaling pathway and other pathways through intracellular calcium release. A recent study implicated GRM1 as playing a role in angiogenesis in hormone receptor negative breast cancer. However, the role of GRM1 in hormone receptor positive disease is yet to be described. Given the associations between melanoma and breast cancer, we evaluated three SNPs in GRM1 for genotype associations with breast cancer clinicopathologic variables using DNA isolated from peripheral blood of 1,096 breast cancer patients. Our study found that a SNP in GRM1 resulting in a proline to serine substitution correlates with age at diagnosis of breast cancer and reflects the receptor status of the breast cancer, e.g. for progesterone receptor positive (PR+) disease, proline carriers were diagnosed 8 years earlier than serine carriers. Genotype-specific associations with risk of developing specific molecular subtypes of breast cancer were observed, i.e. serine carriers were twice as likely to develop estrogen receptor positive (ER+) and PR+ disease. Furthermore, carrying the proline isoform also correlated with higher risk of recurrence of breast cancer and shorter time to recurrence. Immunohistochemical evaluation of breast microarrays showed that GRM1 expression is higher in breast cancers as compared to normal tissue and is higher in ER+ as compared to ER- breast cancers. This parallels higher expression observed in ER+ breast cancer cells lines in comparison to ER- lines. In vitro studies with breast cancer cell lines were also performed to evaluate the expression of GRM1 as a function of hormone exposure and cell line receptor status. Treatment of ER+ cell lines with estradiol resulted in increased GRM1, while tamoxifen decreased expression. Gene expression data on ER+ breast cancers treated with tamoxifen were reanalyzed for association between GRM1 expression and recurrence. Analysis of breast cancers treated with tamoxifen from an independent cohort demonstrated that high expressors of GRM1 have a worse distant recurrence free survival. The results of these studies implicate GRM1 in hormone receptor positive breast cancer biology. Additional knowledge regarding the interaction between GRM1 and hormone signaling could have significant implications in breast cancer risk, prevention, and treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 81. doi:1538-7445.AM2012-81