Therapeutic advances in BIG 3‐ PHB 2 inhibition targeting the crosstalk between estrogen and growth factors in breast cancer

Our previous studies demonstrated that specific inhibition of the BIG 3‐ PHB 2 complex, which is a critical modulator in estrogen (E2) signaling, using ERAP , a dominant negative peptide inhibitor, leads to suppression of E2‐dependent estrogen receptor ( ER ) alpha activation through the reactivation of the tumor suppressive activity of PHB 2. Here, we report that ERAP has significant suppressive effects against synergistic activation caused by the crosstalk between E2 and growth factors associated with intrinsic or acquired resistance to anti‐estrogen tamoxifen in breast cancer cells. Intrinsic PHB 2 released from BIG 3 by ERAP effectively disrupted each interaction of membrane‐associated ER α and insulin‐like growth factor 1 receptor beta ( IGF ‐1Rβ), EGFR , PI 3K or human epidermal growth factor 2 ( HER 2) in the presence of E2 and the growth factors IGF or EGF , followed by inhibited the activation of IGF ‐1Rβ, EGFR or HER 2, and reduced Akt, MAPK and ER α phosphorylation levels, resulting in significant suppression of proliferation of ER α‐positive breast cancer cells in vitro and in vivo . More importantly, combined treatment with ERAP and tamoxifen led to a synergistic suppression of signaling that was activated by crosstalk between E2 and growth factors or HER 2 amplification. Taken together, our findings suggest that the specific inhibition of BIG 3‐ PHB 2 is a novel potential therapeutic approach for the treatment of tamoxifen‐resistant breast cancers activated by the crosstalk between E2 and growth factor signaling, especially in premenopausal women.