Interleukin-6 in the Breast Tumor Microenvironment

Abstract

Greater than 200,000 new cases of breast cancer cases were diagnosed in 2010 in the United States, with approximately 40,000 women succumbing to the disease (www.cancer.gov). Globally, an estimated 1.38 million new cases of breast cancer were diagnosed in 2008, with greater than 450,000 women succumbing to the disease (Jemal et al., 2011). Despite our improved understanding of breast carcinogenesis, breast cancer remains the second most commonly diagnosed cancer in women behind non-melanoma skin cancer and the second leading cause of death in women behind lung cancer. These epidemiological statistics highlight the overwhelming clinical dilemma of breast cancer and emphasize the need for novel therapeutic targets and prevention strategies. Countless studies in the fields of mammary gland development and breast cancer have led to an appreciation of a breast tumor microenvironment that actively contributes to the heterogeneous nature of breast cancer. The current review will focus on the impact of IL-6 and STAT3 activation in the breast tumor microenvironment and subsequently present rationale for targeting the IL6/STAT3 signaling pathway in this setting. IL-6 is a quintessential pleiotropic cytokine produced by a diverse number of cell populations, most of which can localize to the breast tumor microenvironment. Excessive IL-6 has been demonstrated in primary breast tumors and breast cancer patient sera and is associated with poor clinical outcomes in breast cancer. These clinical associations are corroborated by emerging preclinical data revealing that IL-6 is a potent growth factor and promotes an epithelial-mesenchymal (EMT) phenotype in breast cancer cells to indicate that IL-6 in the breast tumor microenvironment is clinically relevant. Numerous clinical reports have now demonstrated the safety and efficacy of IL-6 signaling antagonists in multiple diseases, which supports future investigations of these therapies in breast cancer. Estrogen receptor-alpha (ER┙) is a latent cytoplasmic ligand-activated transcription factor utilized by clinicians to subclassify the heterogeneous disease of breast cancer. ER┙-positive breast cancer incidence increases up to age 51, the mean age of menopause, and continues to increase until age 80. Conversely, ER┙-negative breast cancer incidence plateaus and even slightly decreases at age 51, while demonstrating an increase prior to age 50 comparable to that of ER┙-positive disease. This discrepancy between the two incidence rates at menopause produces an inflection in the incidence rate of all breast cancer cases which has been termed Clemmesen’s hook (Anderson and Matsuno, 2006). Whereas the prevalence of