Chemokine (C-X-C motif) receptor 7 (CXCR7) has been established to be involved in breast cancer (BCa) progression. However, the role of CXCR7 in different subtype of BCa still remains unclear. Here we note that CXCR7 expression is significantly amplified in Luminal type BCa tissues as compared with Her2 and TNBC types through data-mining in TCGA datasets, and its protein level positively correlates with ERα expression by staining of human BCa tissue. Interestingly, alteration of CXCR7 expression in Luminal type BCa cells is able to modulate the expression of ERα through ubiquitination at post-translational level. Additionally, overexpression of CXCR7 in these cells greatly induces 4-OHT insensitivity in vitro and is associated with earlier recurrence in patients with tamoxifen therapy. Notably, silencing ERα expression potentially rescues the sensitivity of the above cells to 4-OHT, suggesting that elevated level of ERα is responsible for CXCR7-induced 4-OHT insensitivity in Luminal type BCa. Finally, mechanistic analyses show that the reduced BRCA1 (ubiquitin E3 ligase) and elevated OTUB1 (deubiquitinase) expression, which are regulated by CXCR7/ERK1/2 signaling pathway, are responsible for stabilizing ERα protein. In conclusion, our results suggest that targeting CXCR7 may serve as a potential therapeutic strategy for improving the efficacy of BCa patients with tamoxifen therapy.