In addition, alterations in the MAPK pathway such as NF1 loss are frequent in endocrine resistant ER+ metastatic breast cancer (31), and contribute to resistance to fulvestrant via both ER-dependent and ER-independent mechanisms (82). Moreover, nuclear RTKs like FGFR1 have also been shown to influence gene expression in ER+ breast cancer and mediate endocrine therapy resistance (83). This evidence concerns the gene ESR1 and breast carcinoma.