Purpose: Wnt signaling occurs in β-catenin-dependent pathways, through β-catenin regulates the expression of many genes, and in the β-catenin-independent planar cell polarity (PCP) and Wnt/Ca2+ pathways. Wnt5a is a key ligand in activation of β-catenin-independent pathways, involved in cell motility and polarity through downstream signaling (e.g., JNK phosphorylation). Wnt5a expression correlates significantly with malignancy and stage of progression in malignant melanoma, gastric cancer, prostate cancer, lung cancer, and pancreatic cancer. In contrast, Wnt5a is a tumor suppressor in colorectal cancer, thyroid cancer, liver cancer, and malignant lymphoma. Thus, the effect of Wnt5a expression differs between organs. The role of Wnt5a expression in breast cancer remains elusive. In this study, we examined significance of Wnt5a expression in breast cancer.

Experimental design: The relationships between Wnt5a expression and clinicopathologic factors were assessed in 178 consecutive cases of invasive breast cancer resected in Hiroshima University Hospital between January 2011 and February 2014. In addition, altered gene expression following Wnt5a addition was mapped as possible Wnt5a-induced transformation pathways.

Results: Wnt5a was positively expressed in 69 of 178 cases (39%) of invasive breast cancer. Wnt5a expression was strongly correlated with estrogen receptor (ER)-positive (P < 0.001). Analysis of the relationship between Wnt5a expression and malignancy in 153 cases of ER-positive breast cancer revealed significant correlations with lymph node metastasis, nuclear grade, and lymphatic invasion. Relapse-free survival was shorter in cases of Wnt5a-positive breast cancer compared to Wnt5a-negative breast cancer cases (P = 0.024). Constitutive expression of Wnt5a in MCF7 cells enhanced migratory capacity, whereas knockdown of Wnt5a reduced this capacity. DNA microarray analysis identified activated leukocyte cell adhesion molecule (ALCAM) as the molecule which is primarily induced by Wnt5a. ALCAM was expressed in 69% of Wnt5a-positive breast cancers but only 27% of Wnt5a-negative breast cancers in 153 cases of ER-positive breast cancer, showing a statistical correlation between Wnt5a and ALCAM expressions. Inhibition of ALCAM in MCF7 constitutively expressing Wnt5a cells reverted the effect of Wnt5a, confirming the important of this molecule in migration of ER-positive breast cancer cells.

Conclusions: In ER-positive breast cancer, Wnt5a expression is related with high malignancy and poor prognosis. We speculate that Wnt5a expression increases malignancy in breast cancer by enhancing migratory capacity of cancer cells through induction of ALCAM expression. Wnt5a may be useful as a predictor of malignancy, a therapeutic target, and a prognostic indicator in ER-positive breast cancer.

Citation Format: Yoshie Kobayashi, Takayuki Kadoya, Ai Amioka, Hideaki Hanaki, Shinsuke Sasada, Norio Masumoto, Koji Arihiro, Akira Kikuchi, Morihito Okada. Effect of Wnt5a on aggressiveness of estrogen receptor-positive breast cancer and cancer cell migration through ALCAM pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 30.