The activity of the estrogen receptors ER1 and ER2 are regulated via interaction with cofactors, among them the steroid receptor coactivator 1 (SRC1). SRC1 has been shown to be a critical regulator of estrogen response. With particular regard to bone, SRC1-/- mice showed osteopenia, and estrogen failed to restore ovariectomy-induced bone loss. There is also evidence that SRC1 may play a role in the response to selective estrogen receptor modulators (SERMs) such as the antiestrogen tamoxifen. Antiestrogens have tissue-specific mixed agonist/antagonist activity, and SRC1 overexpression can result in increased agonist, and decreased antagonist activity in some tissues. Low estrogen levels are associated with decreased bone mineral density (BMD) potentially resulting in osteoporosis. It is known that osteoporosis has a major genetic component, and potential causal genes have been identified. In our studies aimed at examining the role of genetic variants in response to antiestrogens, we recently identified, and subsequently started to characterize, a non-synonymous single nucleotide polymorphism (SNP) in SRC1 (P1272S). Our preliminary data show that the SRC1 P1272S variant displays decreased co-activation of ER, and that is has a shorter half life. In breast cancer patients treated with tamoxifen for 12 months, SNP carriers showed significantly decreased BMD compared to those with wildtype alleles, possibly reflecting a loss of tamoxifen's agonist activity in bone. We hypothesize that the SRC1 P1272S SNP results in decreased ER activity in bone cells, and that this is a result of increased protein turn-over. We also hypothesize that mice harboring the SNP will display osteopenia, and decreased skeletal response to hormone. To address our hypotheses we will i) characterize the effect of the SRC1 SNP on ER activity in bone cells, ii) decipher the mechanism(s) underlying the decreased co-activation activity of the P1272S variant, and iii) generate an SRC1P1278S/P1278S knock-in mouse model, and characterize bone phenotypes. Successful completion of the aims will provide functional data supporting the clinical observation, and would allow strong data for a subsequent R01 submission. Ultimately, we hope that our studies will lead to the further characterization of a SNPs which could be used to "personalize medicine", and in this specific case, to identify people who would benefit from bone-strengthening medications, or other interventions. 1 PUBLIC HEALTH RELEVANCE: We have identified a functional non-synonymous variant in the nuclear receptor cofactor SRC1 which displays decreased coactivation potential, resulting in decreased activity of the estrogen receptor. Collectively, our preliminary data suggest that this SNP could result in increased bone loss. Here we propose to provide further functional support through the analysis of this variant in bone cells, through the study of the underlying mechanism, and finally through the generation and characterization of a mouse knock-in model.