The immune system and inflammation in breast cancer

Abstract

During different stages of tumor development the immune system can either identify and destroy tumors, or promote their growth. Therapies targeting the immune system have emerged as a promising treatment modality for breast cancer, and immunotherapeutic strategies are being examined in preclinical and clinical models. However, our understanding of the complex interplay between cells of the immune system and breast cancer cells is incomplete. In this article, we review recent findings showing how the immune system plays dual host-protective and tumor-promoting roles in breast cancer initiation and progression. We then discuss estrogen receptor α (ERα)-dependent and ERα-independent mechanisms that shield breast cancers from immunosurveillance and enable breast cancer cells to evade immune cell induced apoptosis and produce an immunosuppressive tumor microenvironment. Finally, we discuss protumorigenic inflammation that is induced during tumor progression and therapy, and how inflammation promotes more aggressive phenotypes in ERα positive breast cancers.

Introduction

Despite significant therapeutic achievements in recent years, in industrialized countries, breast cancer remains the most common cancer in women. It causes about 40,000 deaths in the United States each year (Basu et al., 2012). Estrogen receptorα (ERα) positive breast cancers represent more than 70% of breast tumors and endocrine therapies such as selective estrogen receptor modulators (SERMs) and aromatase inhibitors are still the standard adjuvant treatment for these tumors. However, the majority of patients will develop resistance to hormonal therapy and will need alternative therapies (Clarke et al., 2001, Clarke et al., 2003, Osborne and Schiff, 2011).

For over a century, the idea that the immune system can control cancer has been a subject of debate. Only very recently has it become generally accepted that the immune system has the ability not only to prevent tumor growth but also to promote it through a process called immunoediting. This process is comprised of three phases: elimination, equilibrium and escape (Schreiber et al., 2011, Vesely et al., 2011). Elimination is achieved through identification and destruction of nascent transformed cells by acute tumor-inhibiting inflammation, characterized by infiltration of effector cells of the innate and adaptive immune system as well as production of tumor-inhibiting cytokines. The escape phase is sustained by chronic tumor-promoting inflammation, which mainly involves immunosuppressive cells and soluble factors (Vesely et al., 2011). Evading immune destruction has recently been recognized as a hallmark of cancer (Hanahan and Weinberg, 2011). In general, use of immunosuppressants following organ transplantation or HIV infection increases the risk of tumors such as skin cancer, non-Hodgkin’s lymphoma or lung cancers, but not cancers of organs such as breast, brain, prostate and ovary (Kirk et al., 2007, Jiang et al., 2010). These studies suggest that breast cancer cells may be less immunogenic or simply take longer to develop (Vesely et al., 2011). Historically pre-existing inflammation or infection was not considered to be an underlying risk factor for the development of breast cancer. However, it is now clear that the infiltration of leukocytes, in the correct context, can either eliminate or promote the development of breast cancers (DeNardo and Coussens, 2007, Coussens and Pollard, 2011). Several studies have shown that immunity and inflammation-associated gene expression signatures are able to predict or classify tamoxifen-resistant breast cancers (Jansen et al., 2005, Chanrion et al., 2008, Vendrell et al., 2008). This supports the notion that endocrine resistance is associated with a dysregulated immune response and/or excessive inflammation in the tumor microenvironment (Osborne and Schiff, 2011). A recent study suggests that the immune response profile and inflammatory signature in breast cancer may provide useful information on patient prognosis and treatment (Kristensen et al., 2012). These studies suggest that research associated with inflammation and the immune system may enhance therapeutic possibilities for breast cancers, especially for those resistant to endocrine therapies. To better understand the battle and interplay between breast cancer cells and cells of the immune system, in this review we discuss following topics: (1) anti-breast cancer effector cells of the immune system, (2) mechanisms of breast cancer resistance to antitumor immunity, (3) protumorigenic inflammation in breast cancer and (4) inflammation promotion of aggressive phenotypes of ERα positive breast cancer.