ESR1 and breast cancer: In this regard, the compelling evidence to explore the role of E4/GPER axis arise from: (i) the established capacity of this receptor to mediate estrogenic signals in both normal and tumor cells, including breast cancer [12]; (ii) the opposite functions that antiestrogens and certain estrogens (i.e. E3) can elicit through ERα and GPER [13, 18, 19]; (iii) the intriguing question concerning the role played by E4 in ER-negative breast cancer such as TNBC cells.