Molecular targeting of the Aurora-A/SMAD5 oncogenic axis restores chemosensitivity in human breast cancer cells.

Mateusz Opyrchal,Antonino B D’Assoro,Tufia Haddad,Vera Suman,Evanthia Galanis,James N Ingle,James Mccubrey,Mathew P Goetz,Jeffrey L Salisbury,Malgorzata Gil,Ianko Iankov,Amy Degnim,Nicole Shumacher,Chenye B Kurokawa

doi:10.18632/oncotarget.20610

Mateusz Opyrchal, Antonino B D’Assoro + Show 12 more

Open Access

https://doi.org/10.18632/oncotarget.20610

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Abstract

Although the majority of breast cancers initially respond to the cytotoxic effects of chemotherapeutic agents, most breast cancer patients experience tumor relapse and ultimately die because of drug resistance. Breast cancer cells undergoing epithelial to mesenchymal transition (EMT) acquire a CD44+/CD24-/ALDH1+ cancer stem cell-like phenotype characterized by an increased capacity for tumor self-renewal, intrinsic drug resistance and high proclivity to develop distant metastases. We uncovered in human breast tumor xenografts a novel non-mitotic role of Aurora-A kinase in promoting breast cancer metastases through activation of EMT and expansion of breast tumor initiating cells (BTICs). In this study we characterized the role of the Aurora-A/SMAD5 oncogenic axis in the induction of chemoresistance. Breast cancer cells overexpressing Aurora-A showed resistance to conventional chemotherapeutic agents, while treatment with alisertib, a selective Aurora-A kinase inhibitor, restored chemosensitivity. Significantly, SMAD5 expression was required to induce chemoresistance and maintain a breast cancer stem cell-like phenotype, indicating that the Aurora-A/SMAD5 oncogenic axis promotes chemoresistance through activation of stemness signaling. Taken together, these findings identified a novel mechanism of drug resistance through aberrant activation of the non-canonical Aurora-A/SMAD5 oncogenic axis in breast cancer.

Highlights

Tumor relapse associated with distant metastasis is a major cause of death for breast cancer patients [1]
Parental MCF7 and vMCF-7∆Raf1 cells were treated with increased concentration of DR and relative cell proliferation was analyzed after 7 days. vMCF-7∆Raf1 cells exhibited increased resistance to DR treatment when compared to MCF-7 cells (Figure 1A)
Expression of p53 and its downstream transcriptional target p21 was increased following DR treatment in both MCF-7 and vMCF-7∆Raf1 cells (Figure 1D). These results demonstrate that vMCF-7∆Raf1 cells have an intact p53/p21 tumor suppressor axis and increased chemoresistance of vMCF-7∆Raf1 cells is not linked to loss of p53 activity

Summary

Introduction

Tumor relapse associated with distant metastasis is a major cause of death for breast cancer patients [1]. The major hindrances in eradicating metastatic lesions include high tumor cell heterogeneity, self-renewal, and intrinsic resistance to chemotherapeutic agents [2, 3]. ERα and HER2-targeted therapies are ineffective for TNBC [6]. Metastatic ER+ and TNBCs will eventually exhibit resistance to anti-cancer drugs leading to tumor progression and poor outcomes [8,9,10]. A better understanding of the molecular mechanisms responsible for drug resistance is www.impactjournals.com/oncotarget imperative to accelerate the development of innovative strategies to restore chemosensitivity and improve the progression-free and overall survival of breast cancer patients

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