Hydroxychloroquine inhibits autophagy to potentiate antiestrogen responsiveness in ER+ breast cancer.
Hydroxychloroquine inhibits autophagy to potentiate antiestrogen responsiveness in ER+ breast cancer.
复制标题
DOI：
10.1158/1078-0432.ccr-13-3227
复制
发表时间：
2014-06-15
期刊：
影响因子：
--
通讯作者：
Clarke R
中科院分区：
文献类型：
--
作者：
Cook KL;Wärri A;Soto-Pantoja DR;Clarke PA;Cruz MI;Zwart A;Clarke R
雌激素受体-α（ERα）靶向治疗包括他莫昔芬（TAM）或芙仕得（ICI）用于治疗ER+乳腺癌。高达50%的肿瘤会对这些干预措施产生耐药性。自噬被认为是抗雌激素抵抗的主要驱动力。我们已经探索了羟氯喹（HCQ），抑制自噬，影响抗雌激素反应的能力。将TAM抗性MCF 7-RR和ICI抗性/TAM交叉抗性LCC 9 ER+乳腺癌细胞注射到雌性无胸腺小鼠的乳房脂肪垫中，并用TAM和/或ICI与口服低剂量HCQ组合治疗。我们发现HCQ可以增加MCF 7-RR和LCC 9细胞和肿瘤中的抗雌激素反应性，可能是通过抑制自噬。然而，ICI+HCQ的组合在体内不如HCQ单独有效，不像TAM+HCQ组合。抗雌激素治疗刺激肿瘤血管生成，但没有阻止HCQ的有效性。ICI+HCQ的较低疗效与ICI对肿瘤微环境内细胞介导的免疫的影响有关。小鼠趋化因子KC（CXCL 1）和IFNγ受TAM和ICI处理的差异调节，表明可能对巨噬细胞发育/活性产生影响。与这些观察结果一致，TAM+HCQ处理增加了肿瘤CD 68+细胞浸润，而ICI和ICI+HCQ降低了外周肿瘤巨噬细胞含量。此外，巨噬细胞消除乳腺癌靶细胞在体外减少后暴露于ICI。HCQ恢复抗雌激素敏感性耐药肿瘤。此外，TAM+HCQ的有益组合提示使用该组合治疗ER+导管原位癌病变的正在进行的新辅助临床试验的积极结果。
Estrogen receptor-α (ERα) targeted therapies including tamoxifen (TAM) or Faslodex (ICI) are used to treat ER+ breast cancers. Up to 50% of tumors will acquire resistance to these interventions. Autophagy has been implicated as a major driver of antiestrogen resistance. We have explored the ability of hydroxychloroquine (HCQ), which inhibits autophagy, to affect antiestrogen responsiveness. TAM-resistant MCF7-RR and ICI-resistant/TAM cross-resistant LCC9 ER+ breast cancer cells were injected into mammary fat pads of female athymic mice and treated with TAM and/or ICI in combination with oral low-dose HCQ. We show HCQ can increase antiestrogen responsiveness in MCF7-RR and LCC9 cells and tumors, likely through the inhibition of autophagy. However, the combination of ICI+HCQ was less effective than HCQ alone in vivo, unlike the TAM+HCQ combination. Antiestrogen treatment stimulated angiogenesis in tumors but did not prevent HCQ effectiveness. The lower efficacy of ICI+HCQ was associated with ICI effects on cell-mediated immunity within the tumor microenvironment. The mouse chemokine KC (CXCL1) and IFNγ were differentially regulated by both TAM and ICI treatments, suggesting a possible effect on macrophage development/activity. Consistent with these observations, TAM+HCQ treatment increased tumor CD68+ cells infiltration, whereas ICI and ICI+HCQ reduced peripheral tumor macrophage content. Moreover, macrophage elimination of breast cancer target cells in vitro was reduced following exposure to ICI. HCQ restores antiestrogen sensitivity to resistant tumors. Moreover, the beneficial combination of TAM+HCQ suggests a positive outcome for ongoing neoadjuvant clinical trials using this combination for the treatment of ER+ ductal carcinoma in situ lesions.