Format

Send to

Choose Destination
Mol Cancer Res. 2018 Jul 10. doi: 10.1158/1541-7786.MCR-18-0410. [Epub ahead of print]

Taxol Induces Brk-dependent Prosurvival Phenotypes in TNBC Cells through an AhR/GR/HIF-driven Signaling Axis.

Author information

1
Division of Hematology, Oncology, and Transplantation, Departments of Medicine and Pharmacology and The Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
2
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas.
3
Department of Pathology, University of Tennessee Health Science Center, Memphis, Tennessee.
4
Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, NIH, Department of Health and Human Services, Research Triangle Park, North Carolina.
5
Department of Lab Medicine and Pathology, Masonic Cancer Center and Center for Immunology, University of Minnesota, Minneapolis, Minnesota.
6
Division of Hematology, Oncology, and Transplantation, Departments of Medicine and Pharmacology and The Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota. lange047@umn.edu.

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 triple-negative 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. Mol Cancer Res; 1-12. ©2018 AACR.

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center