Division of Endocrinology and Metabolism, Department of Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA.
Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
Mediators Inflamm. 2020 Dec 10;2020:5239419. doi: 10.1155/2020/5239419. eCollection 2020.
Breast cancer results from a complex interplay of genetics and environment that alters immune and inflammatory systems to promote tumorigenesis. Obesity and cigarette smoking are well-known risk factors associated breast cancer development. Nicotine known to decrease inflammatory signals also modulates immune responses that favor breast cancer development. However, the mechanisms by which nicotine and obesity contribute to breast cancer remain poorly understood. In this study, we examined potential mechanisms by which nicotine (NIC) and high-fat diet (HFD) promote growth of HCC70 and HCC1806 xenografts from African American (AA) triple negative (TN) breast cancer cells. Immunodeficient mice fed on HFD and treated with NIC generated larger HCC70 and HCC1806 tumors when compared to NIC or HFD alone. Increased xenograft growth in the presence of NIC and HFD was accompanied by higher levels of tissue-resident macrophage markers and anti-inflammatory cytokines including IL4, IL13, and IL10. We further validated the involvement of these players by and experiments. We found a proinflammatory milieu with increased expression of IL6 and IL12 in xenografts with HFD. In addition, nicotine or nicotine plus HFD increased a subset of mammary cancer stem cells (MCSCs) and key adipose browning markers CD137 and TMEM26. Interestingly, there was upregulation of stress-induced pp38 MAPK and pERK1/2 in xenografts exposed to HFD alone or nicotine plus HFD. Scratch-wound assay showed marked reduction in proliferation/migration of nicotine and palmitate-treated breast cancer cells with mecamylamine (MEC), a nicotine acetylcholine receptor (nAchR) antagonist. Furthermore, xenograft development in immune-deficient mice, fed HFD plus nicotine, was reduced upon cotreatment with MEC and SB 203580, a pp38MAPK inhibitor. Our study demonstrates the presence of nicotine and HFD in facilitating an anti-inflammatory tumor microenvironment that influences breast tumor growth. This study also shows potential efficacy of combination therapy in obese breast cancer patients who smoke.
乳腺癌是遗传和环境复杂相互作用的结果，改变了免疫和炎症系统，促进了肿瘤的发生。肥胖和吸烟是众所周知的与乳腺癌发生相关的风险因素。已知尼古丁可减少炎症信号，也可调节有利于乳腺癌发生的免疫反应。然而，尼古丁和肥胖促进乳腺癌的机制仍知之甚少。在这项研究中，我们研究了尼古丁（NIC）和高脂肪饮食（HFD）促进非洲裔美国人（AA）三阴性（TN）乳腺癌细胞的 HCC70 和 HCC1806 异种移植物生长的潜在机制。在高脂肪饮食和 NIC 治疗下，免疫缺陷小鼠产生的 HCC70 和 HCC1806 肿瘤比 NIC 或 HFD 单独治疗的更大。在 NIC 和 HFD 存在的情况下，异种移植物生长增加伴随着组织驻留巨噬细胞标志物和抗炎细胞因子（包括 IL4、IL13 和 IL10）水平的升高。我们通过 和 实验进一步验证了这些参与者的参与。我们发现高脂肪饮食的异种移植物中存在促炎环境，IL6 和 IL12 的表达增加。此外，尼古丁或尼古丁加 HFD 增加了一组乳腺癌干细胞（MCSCs）和关键脂肪棕色标记物 CD137 和 TMEM26。有趣的是，单独暴露于 HFD 或尼古丁加 HFD 的异种移植物中，应激诱导的 pp38 MAPK 和 pERK1/2 上调。划痕试验表明，尼古丁和棕榈酸处理的乳腺癌细胞在使用烟碱乙酰胆碱受体（nAchR）拮抗剂美金刚胺（MEC）后增殖/迁移明显减少。此外，在高脂肪饮食加尼古丁喂养的免疫缺陷小鼠中，当用 MEC 和 pp38MAPK 抑制剂 SB 203580 联合治疗时，异种移植物的发育减少。我们的研究表明，尼古丁和 HFD 的存在促进了有利于乳腺癌生长的抗炎肿瘤微环境。这项研究还表明，在肥胖吸烟的乳腺癌患者中，联合治疗可能具有潜在疗效。
