Abstract P4-09-17: Wnt5a expression is associated with high-grade malignancy in ER-positive breast cancer

Abstract

Background: Wnt5a is a representative ligand that activates the β-catenin-independent pathways. The purpose of our study is to elucidate the implication of Wnt5a expression in breast cancer. Materials and methods: One hundred seventy eight breast cancer patients (mean age ± SD: 59.6 ± 13.2 years) with clinical Stage I∼III between January 2011 and February 2014, were prospectively evaluated. Patients who underwent operation without neoadjuvant therapy were enrolled to this study. The immunohistochemical analyses of Wnt5a protein was performed to evaluate relationships between Wnt5a expression and clinicopathological factors. MCF7 cells that stably express Wnt5a were generated and used for cDNA microarray analyses to investigate Wnt5a-dependent gene expression. Results: Wnt5a expression was significantly more frequent when estrogen receptor (ER) was present, 68/153 (44%) than when ER was absent, 1/25 (4%) (p<0.001). Wnt5a expression was also related with progesterone receptor (PgR) (P<0.001), but not with HER2 status (P=0.496). In ER-positive breast cancer, a significant interaction between expression of Wnt5a with lymph node metastasis (P<0.001), nuclear grade (P=0.004), lymphatic invasion (P=0.002), vessel invasion (P=0.050), and pStage (P<0.001). Microarray analyses identified several genes induced by Wnt5a (>3.0 fold), involving activated leukocyte cell adhesion molecule (ALCAM). ALCAM is known to be related with apoptosis, invasion and prognosis of breast cancer. Wnt5a expression levels correlated with those of ALCAM in ER-positive tumor samples from patients by immunohistochemical analyses (P<0.001). Relationship between Wnt5a expression and clinicopathological featureClinicopathological featuretotalWnt5a expressionP value (n=153)Negative (n=85)Positive (n=68) Age (median, range) 63, 35-8657.5, 34-870.065Age, n (%) ≤4528 (18)13 (46)15 (54) >45125 (82)72 (58)53 (42)0.282Menopausal status, n (%) Premenopausal58 (38)27 (47)31 (53) Postmenopausal95 (62)58 (61)37 (39)0.080Tumor size, n (%) pT1 ≤20mm104 (44)63 (61)41 (39) pT2/pT3 >20mm49 (56)22 (45)27 (55)0.069lymph node metastasis, n (%) Negative103 (67)72 (70)31 (30) Positive50 (33)13 (26)37 (74)<0.001Nuclear grade, n (%) 1/285 (56)56 (66)29 (34) 368 (44)29 (43)39 (57)0.004Lymphatic invasion, n (%) Negative101 (66)65 (64)36 (36) Positive52 (34)20 (38)32 (62)0.002Vessel invasion, n (%) Negative142 (93)82 (58)60 (42) Positive11 (7)3 (27)8 (73)0.050Ki-67, n (%) 0-2067 (44)43 (64)24 (36) 21-10086 (56)42 (49)44 (51)0.058pStage, n (%) pStage I80 (52)58 (73)22 (28) pStage II64 (42)27 (42)37 (58) pStage III9 (6)0 (0)9 (100)<0.001ALCAM, n (%) Negative85 (56)64 (75)21 (25) Positive68 (44)21 (31)47 (69)<0.001 Conclusions: Wnt5a express in ER-positive breast cancer and are associated with high-grade malignancy. Wnt5a could be a prognostic factor of ER-positive breast cancer. These results have implications that Wnt5a may become a preoperative and postoperative assessment tool for tumor malignancy grade and a potential therapeutic target except endocrine therapy in ER-positive breast cancer. In future studies, further research on Wnt5a are required to develop a novel treatment for more improved outcomes in a great variety of breast cancer. Citation Format: Kobayashi Y, Kadoya T, Gouda N, Kajitani K, Emi A, Shigematsu H, Masumoto N, Okada M. Wnt5a expression is associated with high-grade malignancy in ER-positive breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-09-17.