Discovering New Targets in Triple-Negative Breast Cancer (TNBC): The Androgen Receptor and the Estrogen Receptor β.

Triple-negative breast cancer (TNBC) is a breast cancer (BC) subtype characterized by the lack of estrogen receptor (ER) and progesterone receptor (PR) and the absence of type-2 epidermal growth factor receptor (HER-2) overexpression. This status makes TNBC a challenge for scientists and physicians. Many studies tried to characterize the TNBC to find new targetable proteins to cure this BC subgroup, and the results have certainly underlined its high heterogeneity as principal and undisputed trait. TNBC is usually characterized by poor prognosis, and, to date, chemotherapy is the first-line treatment. Unfortunately, many TNBCs only partially respond to chemotherapy. Many molecules, such as EGFR, PARP, MEK, histone deacetylase (HDAC), heat shock protein 90 (HSP90), and PI3K, are mutated or hyperactivated in TNBC, thereby representing an attractive target to develop effective therapies. Another weakness of TNBC is the presence of a lot of immune cells such as tumor-infiltrating lymphocytes. This makes immunotherapy another fascinating weapon to treat this incurable cancer. To date, many studies have been focused on other two steroid receptors belonging to the nuclear receptor superfamily: the androgen receptor (AR) and the β isoform of estrogen receptor (ERβ). The two receptors represent promising target for controlling growth and spreading of TNBC. The AR and ERβ signaling are complexes and interfere with other cellular pathways hyperactivated in TNBC (EGFR, PI3K, CDKs) thereby strengthening their position and making it the perfect candidate to develop new and effective therapies for TNBC full remission.