The incidence and mortality of breast cancer (BCa) are the highest among female cancers. There are approximate 70% BCa that are classified as estrogen receptor alpha (ERalpha) positive. Therefore, targeting ERalpha is the most significantly therapeutic schedule. However, patients with breast cancer develop resistance to ERalpha or estrogen (E2) antagonists such as fulvestrant and tamoxifen. In the present study, we found that L-Tetrahydropalmatine (L-THP) significantly suppressed cell proliferation in ERalpha(+) BCa cells via inducing cell cycle arrest rather than apoptosis. Additionally, L-THP enhanced the sensitivity of ERalpha(+) BCa cells to tamoxifen and fulvestrant. Mechanically, the application of L-THP promotes ERalpha degradation through accumulating ubiquitin chains on ERalpha. Overexpressing ERalpha abrogates L-THP induced-antiproliferation in ERalpha(+) BCa cells. Collectively, our work indicates that L-THP may represent a potentially novel therapeutic medicine for ERalpha(+) breast cancer patient. CI - (c) The author(s).