Comprehensive immunohistochemical analyses on expression levels of hedgehog signaling molecules in breast cancers.

ABSTRACT

BACKGROUND: The hedgehog (Hh) signaling pathway plays important roles in cell proliferation, malignant progression, invasion and metastasis, and the expansion of cancer stem cells (CSCs). Comprehensive immunohistochemical (IHC) analyses have not yet been conducted on the expression levels of Hh signaling molecules in breast cancer tissues. METHODS: A total of 204 patients with invasive breast cancer treated in our institute were study subjects. IHC analyses on the expression levels of the Hh signaling molecules, sonic Hh (SHH), PTCH1, GLI1, GLI2, and GLI3 and the CSC-related factor, SOX2, were investigated. RESULTS: Positive correlations were observed among all of the Hh signaling molecules tested. SOX2 expression correlated with the expression levels of all Hh signaling molecules. SHH expression positively correlated with tumor size, the Ki-67 labeling index, histological grade, estrogen receptor negativity, progesterone receptor negativity, and HER2 positivity. GLI1 expression positively correlated with the histological grade. GLI2 expression positively correlated with the histological grade, Ki-67 labeling index, and HER2 positivity. Univariate analyses revealed that a younger age, larger tumor size, positive lymph node metastasis, higher histological grade, positive lymphatic invasion, and higher Ki-67 labeling index were related to poor relapse-free survival (RFS). The positivity of all Hh signaling molecules and SOX2 did not correlate with poor RFS. A multivariate analysis revealed that positive lymphatic invasion and a younger age were independent worse prognostic factors for RFS. CONCLUSIONS: This comprehensive analysis demonstrated for the first time that SHH, GLI1, and GLI2 expression levels positively correlated with the malignant phenotypes of tumor cells.