Taken together, these data raised the possibility that BIG3 structurally overlay the KPNAs (KPNA1, KPNA5, and KPNA6) binding region(s) of PHB2 (excluding the ERAP binding region), leading to the inhibition of KPNA-mediated PHB2 nuclear translocation in the presence of E2 in breast cancer cells and resulting in constitutive E2-dependent ERα transcriptional activity. Here, ESR1 is linked to breast cancer.