Prognostic and Therapeutic Implications of Distinct Kinase Expression Patterns in Different Subtypes of Breast Cancer

Abstract

Different kinases are expressed in different clinical subsets of breast cancer. In this study, we assessed kinase expression patterns in different clinical subtypes of breast cancer, evaluated the prognostic and predictive values of kinase metagenes, and investigated their functions in vitro. Four hundred twenty-eight protein kinases in gene expression data were examined from 684 cases of breast cancer and 51 breast cancer cell lines to identify kinase expression patterns. We tested the prognostic value of kinase metagenes in 684 node-negative patients who received no adjuvant therapy and the predictive value in 233 patients who received uniform neoadjuvant chemotherapy. Twelve kinases were overexpressed in estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative, 7 in HER2(+), and 28 in ER(-)/HER2(-) cancers, respectively. We examined the functional role of 22 kinases overexpressed in ER(-)/HER2(-) cancers using siRNA. Downregulation of these kinases caused significant subtype-specific inhibition of cell growth in vitro. Two robust kinase clusters, including an immune kinase cluster and a mitosis kinase cluster, were present in all clinical subgroups. High mitosis kinase score was associated with worse prognosis but higher pathologic complete response (pCR) in ER(+)/HER2(-) cancers, but not in ER(-)/HER2(-) or HER2(+) cancers, in univariate and multivariate analyses including other genomic predictors (MammaPrint, genomic grade index, and the 76-gene signature). Conversely, higher immune kinase score was associated with better survival in ER(+)/HER2(-) and HER2(+) tumors and also predicted higher probability of pCR in HER2(+) cancers. Taken together, our results indicate that kinases regulating mitosis and immune functions convey distinct prognostic information that varies by clinical subtype.