Aurora-A kinase oncogenic signaling mediates TGF-β-induced triple-negative breast cancer plasticity and chemoresistance

Abstract

Triple-negative breast cancer (TNBCs) account for 15–20% of all breast cancers and represent the most aggressive subtype of this malignancy. Early tumor relapse and progression are linked to the enrichment of a sub-fraction of cancer cells, termed breast tumor-initiating cells (BTICs), that undergo epithelial to mesenchymal transition (EMT) and typically exhibit a basal-like CD44high/CD24low and/or ALDH1high phenotype with critical cancer stem-like features such as high self-renewal capacity and intrinsic (de novo) resistance to standard of care chemotherapy. One of the major mechanisms responsible for the intrinsic drug resistance of BTICs is their high ALDH1 activity leading to inhibition of chemotherapy-induced apoptosis. In this study, we demonstrated that aurora-A kinase (AURKA) is required to mediate TGF-β-induced expression of the SNAI1 gene, enrichment of ALDH1high BTICs, self-renewal capacity, and chemoresistance in TNBC experimental models. Significantly, the combination of docetaxel (DTX) with dual TGF-β and AURKA pharmacologic targeting impaired tumor relapse and the emergence of distant metastasis. We also showed in unique chemoresistant TNBC cells isolated from patient-derived TNBC brain metastasis that dual TGF-β and AURKA pharmacologic targeting reversed cancer plasticity and enhanced the sensitivity of TNBC cells to DTX-based-chemotherapy. Taken together, these findings reveal for the first time the critical role of AURKA oncogenic signaling in mediating TGF-β-induced TNBC plasticity, chemoresistance, and tumor progression.

A Novel Five-Gene Signature for Prognosis Prediction in Hepatocellular Carcinoma

“…Blocking the b-catenin pathway and inhibiting AURKA activity at the same time may enhance antitumor response in adrenocortical cancer (25). AURKA was essential for mediating TGF-beta induced plasticity and chemoresistance in triple-negative breast cancer (26). Liu (27) found that knockdown of AURKA could lead to increased radiotherapy efficacy in human colorectal cancer.…”

Knockdown of circSMAD2 inhibits the tumorigenesis of gallbladder cancer through binding with eIF4A3

“…TGF-β signaling plays a crucial role in various tumors, including GBC [ 23 , 24 ]. It has been reported that TGF-β can activate SMAD2 [ 25 , 26 ].…”

Harnessing Carcinoma Cell Plasticity Mediated by TGF-β Signaling

“…One intriguing issue is whether such primed cells are already present in healthy or premalignant epidermal cells as a key factor that engenders the refractoriness of tumor cells to chemotherapies. Other studies also prove that TGF-β-induced EMT is associated with drug resistance in carcinoma [104][105][106]. Thus, targeting TGF-β-related EMT in carcinoma could help to improve the drug efficiency and partially solve resistance issues.…”