Baumgarten Sarah C, Frasor Jonna
Department of Physiology and Biophysics, University of Illinois at Chicago, 835 South Wolcott Avenue, Chicago, IL 60612, USA.
Mol Endocrinol. 2012 Mar;26(3):360-71. doi: 10.1210/me.2011-1302. Epub 2012 Feb 2.
Approximately 75% of breast tumors express the estrogen receptor (ER), and women with these tumors will receive endocrine therapy. Unfortunately, up to 50% of these patients will fail ER-targeted therapies due to either de novo or acquired resistance. ER-positive tumors can be classified based on gene expression profiles into Luminal A- and Luminal B-intrinsic subtypes, with distinctly different responses to endocrine therapy and overall patient outcome. However, the underlying biology causing this tumor heterogeneity has yet to become clear. This review will explore the role of inflammation as a risk factor in breast cancer as well as a player in the development of more aggressive, therapy-resistant ER-positive breast cancers. First, breast cancer risk factors, such as obesity and mammary gland involution after pregnancy, which can foster an inflammatory microenvironment within the breast, will be described. Second, inflammatory components of the tumor microenvironment, including tumor-associated macrophages and proinflammatory cytokines, which can act on nearby breast cancer cells and modulate tumor phenotype, will be explored. Finally, activation of the nuclear factor κB (NF-κB) pathway and its cross talk with ER in the regulation of key genes in the promotion of more aggressive breast cancers will be reviewed. From these multiple lines of evidence, we propose that inflammation may promote more aggressive ER-positive tumors and that combination therapy targeting both inflammation and estrogen production or actions could benefit a significant portion of women whose ER-positive breast tumors fail to respond to endocrine therapy.
大约75%的乳腺肿瘤表达雌激素受体（ER），患有这些肿瘤的女性将接受内分泌治疗。不幸的是，高达50%的这些患者会因原发性或获得性耐药而导致ER靶向治疗失败。ER阳性肿瘤可根据基因表达谱分为Luminal A和Luminal B内在亚型，对内分泌治疗和患者总体预后有明显不同的反应。然而，导致这种肿瘤异质性的潜在生物学机制尚不清楚。本综述将探讨炎症作为乳腺癌风险因素以及在更具侵袭性、对治疗耐药的ER阳性乳腺癌发展过程中的作用。首先，将描述乳腺癌风险因素，如肥胖和妊娠后乳腺 involution，它们可在乳腺内促进炎症微环境。其次，将探讨肿瘤微环境的炎症成分，包括肿瘤相关巨噬细胞和促炎细胞因子，它们可作用于附近的乳腺癌细胞并调节肿瘤表型。最后，将综述核因子κB（NF-κB）途径的激活及其在促进更具侵袭性乳腺癌的关键基因调控中与ER的相互作用。基于这些多方面的证据，我们提出炎症可能促进更具侵袭性的ER阳性肿瘤，针对炎症以及雌激素产生或作用的联合治疗可能使很大一部分ER阳性乳腺肿瘤对内分泌治疗无反应的女性受益。
