Breast cancer is the most common and the most aggressive female cancer. Estrogens play a major role in promoting the proliferation of both normal and neoplastic breast epithelium, and estrogen receptor (ER) – mediated pathways are targeted by anti-cancer drugs, such as tamoxifen that has been long used to treat ER-positive cancers. Several studies revealed the contribution of TRPM7, a cationic channel fused to an alpha-kinase domain on the C-terminus, to cancerogenesis. The results from our Laboratory have demonstrated the involvement of TRPM7 in ER-positive breast cancer cell line MCF-7 proliferation through its channel activity and calcium influx (Guilbert et al., 2009). Here, we investigated (i) the molecular pathways involved in TRPM7-mediated proliferative response of MCF-7 cells, (ii) the role of TRPM7 in estrogen-induced proliferation, and (iii) its expression and activity in MCF-7 cells resistant to Tamoxifen (TAMR). Our data show that down-regulation of TRPM7 in MCF-7 cells by siRNA induces a cell cycle arrest in G2/M phase, concomitant with a decrease in cyclin A, cyclin B, and Cdk1 expression, as well as an activation of Akt but not ERK pathway. Our results do not show any contribution of TRPM7 in basal apoptosis thus excluding this possibility in the above effects. We further investigated the potential involvement of TRPM7 in estrogen-induced proliferation of MCF-7 cells. Our data reveal no additivity or interference between stimulatory effects of estrogen and TRPM7 expression suggesting that estrogen-stimulated proliferation is independent of TRPM7. To investigate further crosstalk between ER pathway and TRPM7, our current efforts are focused on the analysis of proliferative responses in tamoxifen-resistant breast cancer cell line. Our data show that TRPM7 is both overexpressed and overactivated in this cell line. The experiments to determine the role of TRPM7 in proliferation of TAMR cells are ongoing. In conclusion, TRPM7 controls MCF-7 cell proliferation by regulating G2/M phase of the cell cycle, and likely Akt phosphorylation. Moreover, its proliferative role appears to be independent of estrogen stimulation, while its expression and activity are up-regulated in TAMR cells.