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

• Published in: Molecular cancer research 2018-07, Vol.16 (11), p.1761-1772
• Main Authors: 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 N, Lange, Carol A
• Format: Article
• Language: English
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.MCR-18-0410

The metastatic cascade is a complex process that requires cancer cells to survive despite conditions of high physiologic stress. Previously a cooperation between the glucocorticoid receptor (GR) and hypoxia inducible factors (HIFs) 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-FU) 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 pro-survival phenotypes. Mechanistically, AhR and GR co-purified and following chemotherapy and ULA, these factors assembled at the Brk promoter and induced Brk expression in a HIF-dependent manner. Further, 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.