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Destabilization of β-catenin and RAS by targeting the Wnt/β-catenin pathway as a potential treatment for triple-negative breast cancer

 Won-Ji Ryu  ;  Jeong Dong Lee  ;  Jong-Chan Park  ;  Pu-Hyeon Cha  ;  Yong-Hee Cho  ;  Jee Ye Kim  ;  Joo Hyuk Sohn  ;  Soonmyung Paik  ;  Kang-Yell Choi 
 EXPERIMENTAL AND MOLECULAR MEDICINE, Vol.52(5) : 832-842, 2020-05 
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Triple-negative breast cancer (TNBC) is a severe and heterogeneous disease that lacks an approved targeted therapy and has a poor clinical outcome to chemotherapy. Although the RAS-ERK signaling axis is rarely mutated in TNBC, ~50% of TNBCs show an increased copy number and overexpression of epidermal growth factor receptor (EGFR). However, EGFR-targeted therapies have offered no improvement in patient survival, underscoring the need to explore downstream targets, including RAS. We found that both β-catenin and RAS, as well as epidermal growth factor receptor (EGFR), are overexpressed and correlated with one another in tumor tissues of TNBC patients. KYA1797K, an Axin-binding small molecule reducing β-catenin and RAS expression via degradation and suppressing EGFR expression via transcriptional repression, inhibited the proliferation and the metastatic capability of stable cell lines as well as patient-derived cells (PDCs) established from TNBC patient tissues. KYA1797K also suppressed the stemness of 3D-cultured PDCs and xenografted tumors established by using residual tumors from TNBC patients and those established by the TNBC cell line. Targeting both the Wnt/β-catenin and RAS-ERK pathways via small molecules simultaneously reducing the levels of β-catenin, RAS, and EGFR could be a potential therapeutic approach for TNBC.
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1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Paik, Soon Myung(백순명) ORCID logo https://orcid.org/0000-0001-9688-6480
Sohn, Joo Hyuk(손주혁) ORCID logo https://orcid.org/0000-0002-2303-2764
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