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.

• Authors: Mohammad Jalalirad, Tufia C Haddad, Jeffrey L Salisbury, Derek Radisky, Minzhi Zhang, Mark Schroeder, Ann Tuma, Eduard Leof, Jodi M Carter, Amy C Degnim, Judy C Boughey, Jann Sarkaria, Jia Yu, Liewei Wang, Minetta C Liu, Luca Zammataro, Lorenzo Malatino, Evanthia Galanis, James N Ingle, Matthew P Goetz, Antonino B D'Assoro
• Journal: Oncogene (Oncogene) Vol. 40 Issue 14 Pg. 2509-2523 (04 2021) ISSN: 1476-5594 [Electronic] England
• PMID: 33674749 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Aurora Kinase A

Topics

• Aurora Kinase A (metabolism)
• Breast Neoplasms (genetics, mortality)
• Cell Plasticity (genetics)
• Female
• Humans
• Signal Transduction
• Survival Analysis