Minireview: Inflammation: an instigator of more aggressive estrogen receptor (ER) positive breast cancers

Abstract

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.

Fig. 1.

Inflammation promotes an aggressive phenotype of ER-positive tumors. Pregnancy, particularly mammary gland involution, and obesity are known breast cancer risk factors that can promote an inflammatory microenvironment locally within the breast. TAMs (M), adipocytes (A), and fibroblasts (F) within the tumor microenvironment produce both estrogens and cytokines that can activate ER and the NF-κB pathway, respectively, in breast cancer cells. ER and NF-κB can repress or enhance each other's activity at particular genes to promote an aggressive phenotype of ER-positive breast cancer with endocrine therapy resistance, chemoresistance, and increased cell survival and proliferation.