Therapeutic advances in BIG3-PHB2 inhibition targeting the cross-talk between estrogen and growth factors in breast cancer

2016 Fiscal Year Final Research Report

• Project/Area Number: 26461948
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General surgery
• Research Institution: The University of Tokushima
• Principal Investigator: YOSHIMARU Tetsuro 徳島大学, 先端酵素学研究所(プロテオ), 講師 (80424729)
• Co-Investigator(Renkei-kenkyūsha): KATAGIRI Toyomasa 徳島大学, 先端酵素学研究所, 教授 (60291895) ; MIYOSHI Yasuo 兵庫医科大学, 医学部, 教授 (50283784)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: 内分泌療法耐性乳癌 / エストロゲン受容体 / 乳癌 / クロストーク

Outline of Final Research Achievements

We demonstrated that specific inhibitor of the BIG3-PHB2 complex, which is a critical modulator in estrogen (E2) signaling, ERAP, leads to suppression of E2-dependent estrogen-signaling activation. Here, we report that ERAP has significant suppressive effects against synergistic activation caused by the cross-talk between E2 and growth factors associated with intrinsic or acquired resistance to endocrine-therapy in breast cancer cells. Importantly, combined treatment with ERAP and some known anti-estrogen led to a synergistic suppression of signaling that was activated by cross-talk between E2 and growth factors or HER2 amplification. Furthermore, BIG3 overexpression is strongly associated with poor prognosis of breast cancer.
Taken together, our findings suggest that the specific inhibition of BIG3-PHB2 is a novel potential therapeutic approach for the treatment of endocrine-resistant breast cancers activated by the cross-talk between E2 and growth factor signaling.

Free Research Field

乳癌の分子生物学