A total of 70% of breast cancers express the estrogen receptor (ER)α; therefore, targeting the ER may be an effective endocrine therapy with which to inhibit breast cancer growth. Tamoxifen is the most common-used clinically used drug for the treatment of advanced or metastatic ER-positive (ER + ) breast cancer. However, a substantial proportion of patients become resistant to endocrine therapies. To overcome this limitation, in this stud, we sought to maximize the benefits associated with tamoxifen therapy via drug combination strategies. We demonstrated that rapamycin, an FDA-approved mammalian target of rapamycin (mTOR) inhibitor, enhanced the effects of endocrine therapy with tamoxifen, and the concentration of tamoxifen required for ER+ breast cancer cell growth inhibition was substantially reduced. Moreover, treatment with rapamycin plus tamoxifen significantly inhibited tumor growth in vivo. In addition, this synergistic effect may be mediated by the induction of p73. We revealed a novel mechanism in which p73 increases ERα expression by directly binding to the promoter region of the ERα gene. Taken together, the findings of this study indicate that combination therapy with rapamycin and tamoxifen underlying p73-mediated ERα expression may provide new insight into the drug combination for the treatment of ER + breast cancer.