Transcriptional Factor KLF11 is a new prognostic biomarker and potential therapeutic target in human sporadic invasive breast cancer

Abstract

BackgroundBreast cancer (BC) is a heterogeneous disease characterized by distinct molecular subtypes. Krüppel like Factor (KLF) family members in BC have been widely studied. However, the roles of KLFs as tumorpromoters or tumor-suppressors are context-dependent. KLF11, as a member of this family, the expression pattern and prognostic relevance of which in BC remains unclear. MethodsTo clarify whether KLF11 acts as a tumor-promoter or a tumor-suppressor in BC, we explored the prognostic role of the KLF11 in BC patients by performing immunohistochemistry (IHC) staining of KLF11 in 298 patients samples. Then we correlated the expression to clinicopathological characteristics and survival outcomes. To investigate the function of KLF11 in tumor cells, we performed different assays of cell viability, cell proliferation, and cell apoptosis assays in three distinct molecular subtypes of BC cell lines with siRNA-mediated loss-of-function of KLF11. ResultsIn the BC patient cohort, We demonstrated that KLF11 was higher in highly proliferative BC and lowest in luminal A-like BC. Furthermore, "KLF11-high" BC patients had shorter disease-free survival (DFS), distantmetastasis-free survival (DMFS), and local recurrence-free survival (LRFS). High KLF11 expression remained an independent indicator for DFS and DMFS of BC. The multivariate cox regression-dependent, KLF11-related nomograms of DFS and DMFS showed high accuracy in predicting BC patients' 3-,5-and 10 -year survival probability. Our results indicate that KLF11 might play a pro-tumor role in BC.From the KLF11-BC tumor cells perspective, the cellular functional assays con rmed that KLF11 acts as a pro-tumor transcription factor (TF) in BC cells via promoting proliferation and/or decreasing cell apoptosis. However, due to neoplastic intratumor heterogeneity, different cancer molecular subtypes could have different underlying mechanisms. ConclusionsPrior research has demonstrated that KLF11 expression is lower in BC compared to healthy breast tissue.However, we now could show that high KLF11 expression in BC is probably pro-tumorigenic and is associated with an impaired prognosis. Our study indicates that KLF11, as a transcriptional factor, acts as a new prognostic biomarker and might also be potentially a synergistic or an alternative therapeutic target for conventional targeting treatments of human BC. BackgroundBreast cancer (BC) is a malignancy with high mortality among women (1-4). It is a complicated and heterogeneous disease characterized by diverse molecular subtypes. For clinical purposes, BC subtypes are classi ed according to the prognostic biomarkers: estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and the proliferation marker . The cutoff values for high versus low Ki-67 expression vary from 10-29% and remain debatable, thus limiting its clinical utility (6). In recent decades, speci c therapies based on these molecular subtypes-associated parameters, like endocrine therapies for ER-positive or anti-HER2 the...