Abstract
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.
Highlights
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 and Wnt/Ca2+ pathways [1, 2]. β-catenindependent pathways are involved in some cancers, for example, familial polyposis, in which the adenomatous polyposis coli mutation causes the accumulation of β-catenin in the nucleus, resulting in colorectal cancer [2, 3]
Wnt5a is expressed in estrogen receptor (ER)-positive breast cancer
There was no correlation between Wnt5a expression and human epidermal growth factor receptor 2 (HER2) positivity
Summary
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 and Wnt/Ca2+ pathways [1, 2]. β-catenindependent pathways are involved in some cancers, for example, familial polyposis, in which the adenomatous polyposis coli mutation causes the accumulation of β-catenin in the nucleus, resulting in colorectal cancer [2, 3]. While a significant correlation between the immunohistochemical disappearance of Wnt5a expression and poor prognosis [17, 18] has been reported, these studies do not distinguish between breast cancers subtypes. A positive correlation is reported between Wnt5a expression level and ER-positive breast cancer, as determined using breast cancer specimens [17, 18]. Another study reports no significant correlation between the expression of Wnt5a and ER status, as determined by examination of 94 stained breast cancer specimens [22]. Cell motility in Wnt5a-positive gastric cancer is increased through activation of FAK and Rac to induce malignant transformation [7, 8]. Other studies report that Wnt5a expression increases the malignancy of breast cancer through activation of tumor-related macrophages [24] or the promotion of cell migration [25]. We investigate the mechanism of malignant transformation in breast cancer by Wnt5a through biological analyses of cultured cells
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