title: The prognostic significance of Wnt-5a expression in primary breast cancer is extended to premenopausal women.
abstract: Wnt-5a protein expression in primary tumors from unselected breast cancer patients has revealed a tumor suppressive function of the protein. However, in vitro experiments on human breast cancer cells have reported contradictory results, indicating both a tumor suppressive and promoting functions of Wnt-5a. This could be due to various functions of Wnt-5a in different subgroups of patients. The unselected cohorts analyzed to date for Wnt-5a protein expression contained few premenopausal patients. The aim of the present investigation was to evaluate the prognostic significance of Wnt-5a protein expression in a cohort of premenopausal women with comprehensive data on biomarkers, molecular subtypes and long-term outcome. In a randomized trial of adjuvant tamoxifen versus no adjuvant treatment, 564 premenopausal primary breast cancer patients were included. The median follow-up time was 14 years. A tumor tissue array was constructed and 361 samples were evaluated for Wnt-5a reactivity by immunohistochemistry. The primary end-point was recurrence-free survival. Wnt-5a protein expression was reduced or lost in 146/361 of tumors and correlated to younger age, estrogen receptor (ER) negativity and triple-negative phenotype. Wnt-5a was a prognostic factor in the whole cohort (p = 0.003). In patients with ER-positive tumors, Wnt-5a was an independent positive prognostic marker (HR 0.51 95% CI: 0.33-0.78 p = 0.002) and HER2 a negative prognostic marker (HR 2.84 95% CI: 1.51-5.31, p = 0.001) in a Cox multivariate analysis adjusted for standard prognostic markers and tamoxifen treatment. In the ER-negative subset, Wnt-5a added no prognostic information. In a subgroup analysis, Wnt-5a was significantly associated with better prognosis in patients with Luminal A tumors (p = 0.04). Conclusively, our results suggest that loss of Wnt-5a is a valuable prognostic marker in premenopausal breast cancer patients in particular in patients with ER-positive tumors and out-performed conventional prognostic factors in this subset of patients.
authors.affiliation: Experimental Pathology, Department of Laboratory Medicine, Lund University, Skåne University Hospital, Malmö, Sweden ; Surgery, Department of Clinical Sciences Malmö, Lund University, Skåne University Hospital, Malmö, Sweden.
authors.forename: Janna
authors.initials: J
authors.lastname: Sand-Dejmek
authors.forename: Roy
authors.initials: R
authors.lastname: Ehrnström
authors.forename: Pontus
authors.initials: P
authors.lastname: Berglund
authors.forename: Tommy
authors.initials: T
authors.lastname: Andersson
authors.forename: Lisa
authors.initials: L
authors.lastname: Ryden
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003094:Collagen / Q000737:chemistry; D018572:Disease-Free Survival; D004338:Drug Combinations; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D007797:Laminin / Q000737:chemistry; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D009361:Neoplasm Invasiveness; D017697:Premenopause; D011379:Prognosis; D016016:Proportional Hazards Models; D011509:Proteoglycans / Q000737:chemistry; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D016032:Randomized Controlled Trials as Topic; D011960:Receptors, Estrogen / Q000378:metabolism; D013629:Tamoxifen / Q000627:therapeutic use; D046888:Tissue Array Analysis; D016896:Treatment Outcome; D051153:Wnt Proteins / Q000378:metabolism*; D000071818:Wnt-5a Protein
chemical_list: D000970:Antineoplastic Agents; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D011518:Proto-Oncogene Proteins; D011960:Receptors, Estrogen; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D013629:Tamoxifen; C059485:matrigel; D003094:Collagen