Taxol induces brk-dependent prosurvival phenotypes in TNBC cells through an AhR/GR/HIF-driven signaling axis

Tarah M.Regan Anderson, Shihong Ma, Carlos Perez Kerkvliet, Yan Peng, Taylor M. Helle, Raisa I. Krutilina, Ganesh V. Raj, John A. Cidlowski, Julie H. Ostrander, Kathryn L. Schwertfeger, Tiffany Seagroves, Carol A. Lange

Research output: Contribution to journalArticle

Abstract

The metastatic cascade is a complex process that requires cancer cells to survive despite conditions of high physiologic stress. Previously, cooperation between the glucocorticoid receptor (GR) and hypoxia-inducible factors (HIF) was reported as a point of convergence for host and cellular stress signaling. These studies indicated p38 MAPK-dependent phosphorylation of GR on Ser134 and subsequent p-GR/ HIF-dependent induction of breast tumor kinase (PTK6/ Brk), as a mediator of aggressive cancer phenotypes. Herein, p-Ser134 GR was quantified in human primary breast tumors (n = 281) and the levels of p-GR were increased in triplenegative breast cancer (TNBC) relative to luminal breast cancer. Brk was robustly induced following exposure of TNBC model systems to chemotherapeutic agents (Taxol or 5-fluorouracil) and growth in suspension [ultra-low attachment (ULA)]. Notably, both Taxol and ULA resulted in upregulation of the Aryl hydrocarbon receptor (AhR), a known mediator of cancer prosurvival phenotypes. Mechanistically, AhR and GR copurified and following chemotherapy and ULA, these factors assembled at the Brk promoter and induced Brk expression in an HIF-dependent manner. Furthermore, Brk expression was upregulated in Taxol-resistant breast cancer (MCF-7) models. Ultimately, Brk was critical for TNBC cell proliferation and survival during Taxol treatment and in the context of ULA as well as for basal cancer cell migration, acquired biological phenotypes that enable cancer cells to successfully complete the metastatic cascade. These studies nominate AhR as a p-GR binding partner and reveal ways to target epigenetic events such as adaptive and stress-induced acquisition of cancer skill sets required for metastatic cancer spread. Implication: Breast cancer cells enlist intracellular stress response pathways that evade chemotherapy by increasing cancer cell survival and promoting migratory phenotypes.

Original languageEnglish (US)
Pages (from-to)1761-1772
Number of pages12
JournalMolecular Cancer Research
Volume16
Issue number11
DOIs
StatePublished - Nov 1 2018

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Aryl Hydrocarbon Receptors
Glucocorticoid Receptors
Paclitaxel
Breast Neoplasms
Phenotype
Neoplasms
Cell Survival
Drug Therapy
Hypoxia
p38 Mitogen-Activated Protein Kinases
Epigenomics
Fluorouracil
Cell Movement
Suspensions
Phosphotransferases
Up-Regulation
Phosphorylation
Cell Proliferation
Growth

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

Anderson, T. M. R., Ma, S., Kerkvliet, C. P., Peng, Y., Helle, T. M., Krutilina, R. I., ... Lange, C. A. (2018). Taxol induces brk-dependent prosurvival phenotypes in TNBC cells through an AhR/GR/HIF-driven signaling axis. Molecular Cancer Research, 16(11), 1761-1772. https://doi.org/10.1158/1541-7786.MCR-18-0410

Taxol induces brk-dependent prosurvival phenotypes in TNBC cells through an AhR/GR/HIF-driven signaling axis. / Anderson, Tarah M.Regan; Ma, Shihong; Kerkvliet, Carlos Perez; Peng, Yan; Helle, Taylor M.; Krutilina, Raisa I.; Raj, Ganesh V.; Cidlowski, John A.; Ostrander, Julie H.; Schwertfeger, Kathryn L.; Seagroves, Tiffany; Lange, Carol A.

In: Molecular Cancer Research, Vol. 16, No. 11, 01.11.2018, p. 1761-1772.

Research output: Contribution to journalArticle

Anderson, TMR, Ma, S, Kerkvliet, CP, Peng, Y, Helle, TM, Krutilina, RI, Raj, GV, Cidlowski, JA, Ostrander, JH, Schwertfeger, KL, Seagroves, T & Lange, CA 2018, 'Taxol induces brk-dependent prosurvival phenotypes in TNBC cells through an AhR/GR/HIF-driven signaling axis', Molecular Cancer Research, vol. 16, no. 11, pp. 1761-1772. https://doi.org/10.1158/1541-7786.MCR-18-0410
Anderson, Tarah M.Regan ; Ma, Shihong ; Kerkvliet, Carlos Perez ; Peng, Yan ; Helle, Taylor M. ; Krutilina, Raisa I. ; Raj, Ganesh V. ; Cidlowski, John A. ; Ostrander, Julie H. ; Schwertfeger, Kathryn L. ; Seagroves, Tiffany ; Lange, Carol A. / Taxol induces brk-dependent prosurvival phenotypes in TNBC cells through an AhR/GR/HIF-driven signaling axis. In: Molecular Cancer Research. 2018 ; Vol. 16, No. 11. pp. 1761-1772.
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AU - Ma, Shihong

AU - Kerkvliet, Carlos Perez

AU - Peng, Yan

AU - Helle, Taylor M.

AU - Krutilina, Raisa I.

AU - Raj, Ganesh V.

AU - Cidlowski, John A.

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AU - Seagroves, Tiffany

AU - Lange, Carol A.

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