Estrogen receptor (ER)α is expressed in approximately 75% of breast tumors at the time of diagnosis, and ER status serves as a major prognostic marker and determinant of the course of therapy that a patient will receive. Patients with ER-positive tumors generally have a better prognosis than those with tumors that lack ER, and these patients usually undergo treatment with endocrine therapy such as the selective ER modulator (SERM) tamoxifen or aromatase inhibitors. Unfortunately, many patients with ER-positive tumors fail to respond to endocrine therapy, and most tumors that are initially responsive acquire resistance (1). These tumors typically continue to express ER (2) and demonstrate earlier metastatic recurrence (3). Currently, there is still no clear method to distinguish tumors that will or will not respond to endocrine therapy. As a result, one goal of research efforts is to find predictive markers so that women with ER-positive tumors can be treated appropriately, meaning that women with tumors that are most likely to respond to endocrine therapy can avoid detrimental overtreatment, whereas women whose tumors are least likely to respond will receive more aggressive chemotherapies earlier.
In recent years, numerous studies using gene expression profiling have attempted to uncover signatures that predict response to endocrine therapy to steer women into more appropriate therapeutic avenues. For example, profiling of ER-positive tumors has led to a number of signatures that are predictive of clinical outcome for patients taking tamoxifen (4, 5). In broader gene profiling studies of both ER-positive and ER-negative breast tumors, ER-positive tumors were classified into two intrinsic subtypes, Luminal A and Luminal B, that differ significantly in relapse-free and overall survival (6). Tumors of the Luminal A subtype are associated with greater overall patient survival, whereas the Luminal B subtype is associated with significantly worse patient outcome. These findings led to the development of the PAM50 Breast Cancer Intrinsic Classifier assay that uses expression levels of 50 genes to classify the intrinsic tumor subtype, including Luminal A and Luminal B, and can provide additional predictive and prognostic information beyond current pathological tumor characterization (7, 8). Another multigene assay, called Oncotype DX, has been developed to predict recurrence risk within 10 yr of diagnosis for patients with node negative, ER-positive, stage I or II invasive breast cancer. Expression levels of 16 cancer-related genes and five control genes are used to quantify the likelihood of recurrence (9) and predict the benefit that a patient with an ER-positive tumor may gain from adjuvant chemotherapy treatment (10, 11).
Although gene expression studies have the potential to provide greater predictive ability for responsiveness of some ER-positive breast tumors to endocrine therapy, the underlying biology causing tumor heterogeneity has yet to become fully clear. What is known is that ER-positive tumors with poor response to endocrine therapy tend to have lower ER expression (12, 13), low to no progesterone receptor expression (14, 15), and high levels of proliferation-associated genes (4, 16). One accepted mechanism of resistance to endocrine therapy is overexpression of human epidermal growth factor receptor 2 (HER2) but this occurs in only 10% of ER-positive breast cancers (17–19). A number of studies suggest that other growth factors and signaling pathways, such as IGF-I, phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT), and protein kinase C alpha (PKCα), contribute to poor outcome for women with ER-positive tumors (13, 20–24). Current thinking is that human epidermal growth factor receptor 2 (HER2) signaling or activation of these other pathways can either override or alter ER activity, such that tamoxifen or aromatase inhibitors are no longer effective. Thus, a number of mechanisms have been proposed to contribute to tumor escape from endocrine therapy, suggesting that the etiology of endocrine resistance may be multifactorial. In this review, we will explore inflammation as another biological factor that may cause increased risk of ER-positive breast cancer and/or poor therapeutic response to endocrine therapy.
Inflammation is now considered a hallmark of cancer (25) and can play a role in virtually all aspects of tumor biology, including initiation, promotion, angiogenesis, and metastasis (26). An inflammatory tumor microenvironment consists of infiltrating immune cells and activated fibroblasts, both of which can secrete cytokines, chemokines, and growth factors, as well as DNA-damaging agents (27). Downstream of cytokines and chemokines, the nuclear factor κB (NF-κB) pathway is known to be a major player in many aspects of tumor biology (28). Tumors themselves are able to both generate and respond to inflammatory microenvironments (26). Oncogenic changes within the tumor, hypoxia, secretion of molecules that attract inflammatory cells, and the extensive tumor cell death and necrosis initiated by cancer therapy are all contributors to an inflammatory microenvironment. Additionally, factors outside of the tumor, such as obesity, can create an inflammatory environment that contributes to tumorigenesis.
The structural and cellular composition of the breast provides a unique microenvironment for both tumor growth and localized inflammation. Hormonally responsive epithelial cells with specialized functions for milk production and ejection, along with many types of stromal and immune cells, are embedded in adipose tissue, which is now clearly recognized as both an endocrine and an inflammatory organ (29). In this review, several lines of clinical, preclinical, and cell-based evidence will be presented that suggest that an inflammatory microenvironment in the breast may be both a mediator of various risk factors associated with breast cancer as well as a player in the development of more aggressive breast tumors that fail to respond to therapies. More specifically, two risk factors, mammary gland involution, after pregnancy, and obesity, and their ability to create an inflammatory tumor microenvironment, will be discussed (Fig. 1). In addition, the ability of locally produced estrogens and proinflammatory cytokines, and subsequent activation of ER and NF-κB transcription factors, to promote a more aggressive ER-positive breast tumor phenotype will be reviewed. We will focus on the role of inflammation in ER-positive cancers, because studies have shown that regular use of nonsteroidal antiinflammatory drugs (NSAIDS), such as aspirin, significantly reduce the risk of ER-positive but not ER-negative breast cancers (30). Furthermore, although there is an inverse correlation between most markers of inflammation and ER, those ER-positive tumors with an inflammatory component tend to be more aggressive and are associated with a poor outcome and therapeutic failure.