Patients with estrogen receptor α positive (ERα⁺) breast cancer can respond to endocrine therapy, but treatment resistance is common and associated with downregulation of ERα expression in the dormant residual cells. Here we show, using long-term NSG xenograft models of human breast cancer and primary human monocytes, in vitro primary cell cultures and tumors from breast cancer patients, that macrophage derived tumor necrosis factor alpha (TNFα) downregulates ERα in breast cancer cells via inactivation of the transcription factor Forkhead box O transcription factor 3a (FOXO3a). Moreover, presence of tumor associated macrophages in the primary tumor of breast cancer patients, was associated with ERα negativity, and with worse prognosis in patients with ERα⁺ tumors. We propose that pro-inflammatory macrophages, despite being tumoricidal, may have direct effects on tumor progression and endocrine resistance in breast cancer patients. Our findings suggest that TNFα antagonists should be evaluated for treatment of ERα⁺ breast cancer.

雌激素受体α阳性（ERα ⁺）乳腺癌的患者可以对内分泌治疗产生反应，但是治疗耐药性很普遍，并且与休眠残留细胞中ERα表达的下调有关。在这里，我们显示，使用人类乳腺癌和原代人单核细胞的长期NSG异种移植模型，体外原代细胞培养和乳腺癌患者的肿瘤，巨噬细胞衍生的肿瘤坏死因子α（TNFα）通过失活下调了乳腺癌细胞中的ERα。转录因子叉头盒O转录因子3a（FOXO3a）的表达。此外，在乳腺癌患者的原发性肿瘤中存在与肿瘤相关的巨噬细胞，与ERα阴性有关，并且与ERα ⁺患者的预后较差肿瘤。我们提出，促炎性巨噬细胞尽管具有杀肿瘤性，但可能对乳腺癌患者的肿瘤进展和内分泌抵抗力具有直接影响。我们的发现表明，应评估TNFα拮抗剂对ERα ⁺乳腺癌的治疗。