Purpose: We previously showed that Wnt5a-positive breast cancer belongs to a subgroup of estrogen receptor (ER)-positive breast cancers and its prognosis is worse than that of Wnt5a-negative breast cancer. In this study, we aimed to investigate the molecular mechanisms underlying the poor prognosis of patients with Wnt5a-positive breast cancer.Methods: A total of 151 patients with ER-positive invasive breast cancer were recruited for this study between January 2011 and February 2014. The association between Wnt5a expression and recurrence rate was examined. To identify the pathways associated with Wnt5a-positive breast cancer, we established a Wnt5a-expressing cell line (MCF-7/Wnt5a cells) and conducted DNA microarray analysis of MCF-7/Wnt5a cells. We also performed pathway analysis associated with Wnt5a expression, and evaluated the effects of Wnt5a in vitro using MCF-7/Wnt5a cells.Results: Data showed poorer relapse-free survival of patients with Wnt5a-positive breast cancer (P = 0.047). The median length of follow-up was 6.08 years (range, 0.027 to 8.47 years) for all patients. According to DNA microarray data, only the cytochrome P450 (CYP) pathway was significantly upregulated and related with Wnt5a (P = 0.0440). Moreover, MCF-7/Wnt5a cells were less sensitive to tamoxifen and paclitaxel, which are metabolic substrates of CYP (P < 0.05). Although the PI3K-AKT-mTOR signaling pathway is involved in the poor prognosis of ER-positive breast cancer, it was not associated with Wnt5a.Conclusions: In ER-positive breast cancer, Wnt5a expression upregulated the CYP metabolic pathway and decreased the sensitivity to tamoxifen and paclitaxel, the standard treatment options for ER-positive breast cancer.

Citation Format: Ai Amioka, Takayuki Kadoya, Satoshi Sueoka, Yoshie Kobayashi, Shinsuke Sasada, Akiko Emi, Norio Masumoto, Masaoki Ito, Morihito Okada. Effect of Wnt5a on drug resistance in estrogen receptor-positive breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS19-23.