Cancer Immunology, Department of Translational Medicine, 214 28, Malmö, Lund University, Sweden.
Cancer Immunology, Department of Translational Medicine, 214 28, Malmö, Lund University, Sweden; Division of Clinical Genetics, Department of Laboratory Medicine Lund, Lund University, 221 00, Lund, Sweden.
Exp Cell Res. 2020 May 1;390(1):111932. doi: 10.1016/j.yexcr.2020.111932. Epub 2020 Mar 4.
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）乳腺癌患者可以对内分泌治疗产生反应，但治疗耐药性很常见，与休眠残留细胞中 ERα 表达下调有关。在这里，我们使用人乳腺癌的长期 NSG 异种移植模型、原代人单核细胞、体外原代细胞培养物和乳腺癌患者的肿瘤，表明巨噬细胞衍生的肿瘤坏死因子 α（TNFα）通过失活转录因子叉头框 O 转录因子 3a（FOXO3a）下调乳腺癌细胞中的 ERα。此外，乳腺癌患者原发肿瘤中存在肿瘤相关巨噬细胞与 ERα 阴性以及 ERα 肿瘤患者预后较差相关。我们提出，尽管促炎巨噬细胞具有杀瘤作用，但它们可能对乳腺癌患者的肿瘤进展和内分泌耐药性有直接影响。我们的研究结果表明，应评估 TNFα 拮抗剂治疗 ERα 乳腺癌的疗效。
