Heterogeneity in hormone-dependent breast cancer and therapy: Steroid hormones, HER2, melanoma antigens, and cannabinoid receptors

Breast cancer is the most frequently diagnosed cancer and the leading cause of death by cancer among women worldwide. The prognosis of the disease and patients’ response to different types of therapies varies in different subgroups of this heterogeneous disease. The subgroups are based on histological and molecular characteristics of the tumor, especially the expression of estrogen (ER) and progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Hormone-dependent breast cancer, determined predominantly by the presence of ER, is the most common type of breast cancer. Patients with hormone-dependent breast cancer have an available targeted therapy, however, tumor cells can develop resistance to the therapy, which is a major obstacle limiting the success of treatment and enabling relapse to metastatic disease. The complicated crosstalk of both tumor-intrinsic and exogenous factors may contribute to endocrine resistance, although the underlying molecular details are still enigmatic. For example, the expression of the melanoma antigen genes (MAGE) correlates with a worse clinical prognosis and therapy resistance in many types of cancers, including breast cancer. Recent studies suggested that cancers co-opt MAGEs’ physiological functions to promote therapy resistance and potentially metastasis development. The response to the therapy can be also affected by the concurrent use of alternative therapy, e.g., cannabinoid use is popular among breast cancer patients. Cannabinoids interact with endogenous estrogen function, however, how they interfere with breast cancer therapy is still poorly understood. In this review, we summarize the role of ER, PR, and HER2 in hormone-dependent breast cancer; provide current knowledge of MAGEs and cannabinoid receptors in breast cancer; ultimately discuss the potential interlacement of their signaling paths which may underlay diverse responses to therapies in breast cancer patients simultaneously using cannabinoids. These interactions are poorly understood but critical for the advancement of conventional and complementary treatment options for patients, particularly the ones with metastatic disease.