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

Mateusz Opyrchal, Gil Malgorzata, Jeffrey L Salisbury, Matthew Philip Goetz, Vera Jean Suman, Amy C Degnim, James McCubrey, Tufia C Haddad, Ianko Iankov, Chenye B. Kurokawa, Nicole Shumacher, James N. Ingle, Evanthia Galanis, Antonio D'Assoro

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)91803-91816
Number of pages14
JournalOncotarget
Volume8
Issue number53
DOIs
StatePublished - 2017

Fingerprint

Breast Neoplasms
Neoplastic Stem Cells
Aurora Kinase A
Drug Resistance
Epithelial-Mesenchymal Transition
Neoplasm Metastasis
Phenotype
Heterografts
Neoplasms
Recurrence

Keywords

  • Breast cancer
  • Chemoresistance
  • EMT
  • Stemness
  • Tumor progrression

ASJC Scopus subject areas

  • Oncology

Cite this

Molecular targeting of the Aurora-A/SMAD5 oncogenic axis restores chemosensitivity in human breast cancer cells. / Opyrchal, Mateusz; Malgorzata, Gil; Salisbury, Jeffrey L; Goetz, Matthew Philip; Suman, Vera Jean; Degnim, Amy C; McCubrey, James; Haddad, Tufia C; Iankov, Ianko; Kurokawa, Chenye B.; Shumacher, Nicole; Ingle, James N.; Galanis, Evanthia; D'Assoro, Antonio.

In: Oncotarget, Vol. 8, No. 53, 2017, p. 91803-91816.

Research output: Contribution to journalArticle

Opyrchal, Mateusz ; Malgorzata, Gil ; Salisbury, Jeffrey L ; Goetz, Matthew Philip ; Suman, Vera Jean ; Degnim, Amy C ; McCubrey, James ; Haddad, Tufia C ; Iankov, Ianko ; Kurokawa, Chenye B. ; Shumacher, Nicole ; Ingle, James N. ; Galanis, Evanthia ; D'Assoro, Antonio. / Molecular targeting of the Aurora-A/SMAD5 oncogenic axis restores chemosensitivity in human breast cancer cells. In: Oncotarget. 2017 ; Vol. 8, No. 53. pp. 91803-91816.
@article{d65267989324448ebba306879a2fb69f,
title = "Molecular targeting of the Aurora-A/SMAD5 oncogenic axis restores chemosensitivity in human breast cancer cells",
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.",
keywords = "Breast cancer, Chemoresistance, EMT, Stemness, Tumor progrression",
author = "Mateusz Opyrchal and Gil Malgorzata and Salisbury, {Jeffrey L} and Goetz, {Matthew Philip} and Suman, {Vera Jean} and Degnim, {Amy C} and James McCubrey and Haddad, {Tufia C} and Ianko Iankov and Kurokawa, {Chenye B.} and Nicole Shumacher and Ingle, {James N.} and Evanthia Galanis and Antonio D'Assoro",
year = "2017",
doi = "10.18632/oncotarget.20610",
language = "English (US)",
volume = "8",
pages = "91803--91816",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "53",

}

TY - JOUR

T1 - Molecular targeting of the Aurora-A/SMAD5 oncogenic axis restores chemosensitivity in human breast cancer cells

AU - Opyrchal, Mateusz

AU - Malgorzata, Gil

AU - Salisbury, Jeffrey L

AU - Goetz, Matthew Philip

AU - Suman, Vera Jean

AU - Degnim, Amy C

AU - McCubrey, James

AU - Haddad, Tufia C

AU - Iankov, Ianko

AU - Kurokawa, Chenye B.

AU - Shumacher, Nicole

AU - Ingle, James N.

AU - Galanis, Evanthia

AU - D'Assoro, Antonio

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

KW - Breast cancer

KW - Chemoresistance

KW - EMT

KW - Stemness

KW - Tumor progrression

UR - http://www.scopus.com/inward/record.url?scp=85032623959&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85032623959&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.20610

DO - 10.18632/oncotarget.20610

M3 - Article

VL - 8

SP - 91803

EP - 91816

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 53

ER -