Research Papers:

Wnt5a-induced cell migration is associated with the aggressiveness of estrogen receptor-positive breast cancer

Yoshie Kobayashi, Takayuki Kadoya _, Ai Amioka, Hideaki Hanaki, Shinsuke Sasada, Norio Masumoto, Hideki Yamamoto, Koji Arihiro, Akira Kikuchi and Morihito Okada

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Oncotarget. 2018; 9:20979-20992. https://doi.org/10.18632/oncotarget.24761

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Yoshie Kobayashi1, Takayuki Kadoya1, Ai Amioka1, Hideaki Hanaki1, Shinsuke Sasada1, Norio Masumoto1, Hideki Yamamoto2, Koji Arihiro3, Akira Kikuchi2 and Morihito Okada1

1Department of Surgical Oncology, Research Center for Radiation Casualty Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Minami-ku, Hiroshima, 734-8551, Japan

2Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan

3Department of Anatomical Pathology, Hiroshima University Hospital, Minami-ku, Hiroshima, 734-8551, Japan

Correspondence to:

Takayuki Kadoya, email: [email protected]

Keywords: Wnt5a; ER-positive breast cancer; cell migration; activated leukocyte cell adhesion molecule; prognosis

Received: August 25, 2017     Accepted: February 26, 2018     Published: April 20, 2018


Elevated expression of Wnt5a is associated with malignancy, cell invasion, and metastasis. The role of Wnt5a expression in breast cancer remains elusive. We investigated the significance of Wnt5a expression in breast cancer. The relationship between Wnt5a expression and clinicopathologic factors was assessed in invasive breast cancer (n = 178) resected at Hiroshima University Hospital between January 2011 and February 2014. Wnt5a was expressed in 69 of 178 cases (39%) of invasive breast cancer and correlated strongly with estrogen receptor (ER) expression (P < 0.001). Wnt5a expression in ER-positive breast cancer correlated significantly with lymph node metastasis, nuclear grade, and lymphatic invasion. The recurrence-free survival was shorter in breast cancer patients with Wnt5a expression than in those without (P = 0.024). The migratory capacity of ER-positive breast cancer cells increased with constitutive expression of Wnt5a and decreased with Wnt5a knockdown. DNA microarray analysis identified activated leukocyte cell adhesion molecule (ALCAM) as the primary gene induced by Wnt5a. ALCAM was expressed in 69% of Wnt5a-positive but only 27% of Wnt5a-negative cancers (κ = 0.444; P < 0.001). The inhibition of ALCAM reversed the enhanced migratory effect of Wnt5a, confirming the importance of this protein in the migration of ER-positive breast cancer cells. Wnt5a expression is related to high malignancy and a poor prognosis in ER-positive breast cancer. We suspect that Wnt5a expression increases the malignancy of breast cancer by increasing the migratory capacity of cancer cells through the induction of ALCAM expression.

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