Center for Gender Specific Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy.
Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy.
Cells. 2019 Jul 19;8(7):750. doi: 10.3390/cells8070750.
Tamoxifen resistance is a major hurdle in the treatment of estrogen receptor (ER)-positive breast cancer. The mechanisms of tamoxifen resistance are not fully understood although several underlying molecular events have been suggested. Recently, we identified autoantibodies reacting with membrane-associated ERα (anti-ERα Abs) in sera of breast cancer patients, able to promote tumor growth. Here, we investigated whether anti-ERα Abs purified from sera of ER-positive breast cancer patients could contribute to tamoxifen resistance. Anti-ERα Abs inhibited tamoxifen-mediated effects on cell cycle and proliferation in MCF-7 cells. Moreover, anti-ERα Abs hampered the tamoxifen-mediated reduction of tumor growth in SCID mice xenografted with breast tumor. Notably, simvastatin-mediated disaggregation of lipid rafts, where membrane-associated ERα is embedded, restored tamoxifen sensitivity, preventing anti-ERα Abs effects. In conclusion, detection of serum anti-ERα Abs may help predict tamoxifen resistance and concur to appropriately inform therapeutic decisions concerning hormone therapy in ER-positive breast cancer patients.
他莫昔芬耐药是治疗雌激素受体（ER）阳性乳腺癌的主要障碍。虽然已经提出了几种潜在的分子事件，但他莫昔芬耐药的机制仍不完全清楚。最近，我们在乳腺癌患者的血清中鉴定出与膜结合的 ERα 反应的自身抗体（抗 ERα Abs），能够促进肿瘤生长。在这里，我们研究了从 ER 阳性乳腺癌患者血清中纯化的抗 ERα Abs 是否有助于他莫昔芬耐药。抗 ERα Abs 抑制了 MCF-7 细胞中他莫昔芬介导的细胞周期和增殖作用。此外，抗 ERα Abs 阻碍了他莫昔芬介导的对 SCID 小鼠异种移植乳腺癌的肿瘤生长的抑制作用。值得注意的是，辛伐他汀介导的脂筏解聚，其中嵌入了膜结合的 ERα，恢复了他莫昔芬的敏感性，阻止了抗 ERα Abs 的作用。总之，检测血清中的抗 ERα Abs 可能有助于预测他莫昔芬耐药，并有助于为 ER 阳性乳腺癌患者的激素治疗提供适当的治疗决策信息。
