ABSTRACT
Receptor activator of NF-κB (RANK) and its ligand, RANKL, are essential for osteoclastogenesis and modulate osteolytic bone metastasis. The RANKL/RANK system is also fundamental for mammary gland development and plays a potential role in breast carcinogenesis. c-Src, a nonreceptor tyrosine kinase downstream of RANK, is overexpressed in most breast cancers and plays a key role in several transduction pathways. The aim of the study was to examine the expression of these molecules in tissue microarrays constructed from 62 advanced breast cancers and 10 breast cancers controls (no metastasis after follow-up). Significantly higher levels of RANK and lower levels of RANKL were found in triple-negative (ER-/PR-/HER2-) tumors when compared with luminal subtypes, whereas their levels in the HER2 subtype were quantitatively in between. RANK expression was significantly associated with tumor grade/differentiation by multivariate analysis. Despite their high expression in bone, neither molecule in primary tumors seemed to be related to a bone-seeking phenotype. Rather, they were significantly correlated with a brain-metastatic phenotype. RANKL and RANK were significantly associated with survival outcomes. Further, Src expression showed a significantly positive linear relationship with RANK, suggesting a potential mechanism of the RANKL-RANK axis in regulating breast cancer cell differentiation and antiapoptosis. Thus, these molecules may be potential therapeutic targets, especially in triple-negative tumors, for which the only systemic treatment option is cytotoxic chemotherapy.
Subject(s)
Bone Neoplasms/diagnosis , Brain Neoplasms/diagnosis , Breast Neoplasms/diagnosis , Carcinoma, Ductal, Breast/diagnosis , RANK Ligand/genetics , Receptor Activator of Nuclear Factor-kappa B/genetics , src-Family Kinases/genetics , Adult , Aged , Aged, 80 and over , Bone Neoplasms/genetics , Bone Neoplasms/mortality , Bone Neoplasms/secondary , Brain Neoplasms/genetics , Brain Neoplasms/mortality , Brain Neoplasms/secondary , Breast Neoplasms/genetics , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Carcinoma, Ductal, Breast/genetics , Carcinoma, Ductal, Breast/mortality , Carcinoma, Ductal, Breast/secondary , Cell Differentiation , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/metabolism , Cell Transformation, Neoplastic/pathology , Estrogen Receptor alpha/deficiency , Estrogen Receptor alpha/genetics , Female , Gene Expression Regulation, Neoplastic , Humans , Middle Aged , Neoplasm Grading , Neoplasm Staging , RANK Ligand/metabolism , Receptor Activator of Nuclear Factor-kappa B/metabolism , Receptor, ErbB-2/deficiency , Receptor, ErbB-2/genetics , Receptors, Progesterone/deficiency , Receptors, Progesterone/genetics , Signal Transduction , Survival Analysis , Tissue Array Analysis , src-Family Kinases/metabolismABSTRACT
Breast-conserving surgery with radiation therapy has become a standard treatment option in women with localized ductal carcinoma in situ. Re-excision is common in breast-conserving surgery, partly due to lack of consensus on what might constitute an adequate margin. In this study, we aimed to identify potential predictive factors for presence/absence of residual disease after initial breast-conserving surgery. Of 232 cases with a diagnosis of ductal carcinoma in situ without invasive carcinoma at initial biopsy between 2005 and 2009, 108 patients underwent breast-conserving surgery, of which 46 had re-excisions due to close margins (≤ 2 mm). The notable features significantly associated with ductal carcinoma in situ residuum (19/46; 41%) on univariate logistic regression analysis included the number of close margins, the percentage of sections with ductal carcinoma in situ, and the number of duct spaces with ductal carcinoma in situ (no. of ductal carcinoma in situ ducts) at close margins. Only the percentage of sections with ductal carcinoma in situ remained a significant factor associated with outcomes on multivariate analysis, whereas the number of ductal carcinoma in situ ducts at close margins held borderline predictive value (P = .054). Furthermore, logistic regression and classification and regression tree analysis using the 10-fold cross validation method revealed optimal predicting accuracy by using the 3 significant factors in univariate analysis. The final decision tree was constructed by using the number of ductal carcinoma in situ ducts at close margins and the percentage of sections with ductal carcinoma in situ. Thus, these 2 factors represent the most powerful predictors for residual disease on re-excision. Optimal discriminatory power for prediction of absence of residual disease was achieved with cutoffs of 18 ductal carcinoma in situ ducts at close margins and 51.3% sections with ductal carcinoma in situ.
