FOXC1 and SOX10 in Estrogen Receptor–Low Positive/HER2-Negative Breast Cancer: Potential Biomarkers for the Basal-like Phenotype Prediction

Abstract

Context.— Breast cancer with low (1%–10%) estrogen receptor (ER) expression (ER–low positive) constitutes a small portion of invasive breast cancers, and the treatment strategy for these tumors remains debatable. Objective.— To characterize the features and outcomes of ER–low positive patients, and clarify the clinical significance of FOXC1 and SOX10 expression in ER–low positive/HER2-negative tumors. Design.— Among 9082 patients diagnosed with primary invasive breast cancer, the clinicopathologic features of those with ER–low positive breast cancer were characterized. FOXC1 and SOX10 mRNA levels were analyzed in ER–low positive/HER2-negative cases from public data sets. The expression of FOXC1 and SOX10 in ER–low positive/HER2-negative tumors was evaluated by immunohistochemistry. Results.— The clinicopathologic study of ER–low positive tumors indicated more aggressive characteristics compared with those tumors with ER >10%, while they had more overlapping features with ER-negative tumors irrespective of the HER2 status. The intrinsic molecular subtype of ER–low positive cases with high FOXC1 and SOX10 mRNA expression was more likely to be nonluminal. Among the ER–low positive/HER2-negative tumors, 56.67% (51 of 90) and 36.67% (33 of 90) were positive for FOXC1 and SOX10, respectively, which was significantly positively correlated with CK5/6 expression. In addition, the survival analysis demonstrated no significant difference between patients who received and who did not receive endocrine therapy. Conclusions.— ER–low positive breast cancers biologically overlap more with ER-negative tumors. ER–low positive/HER2-negative cases demonstrate a high rate of FOXC1 or SOX10 expression, and these cases might be better categorized as a basal-like phenotype/subtype. FOXC1 and SOX10 testing may be used for the intrinsic phenotype prediction for ER–low positive/HER2-negative patients.