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.
Bibliographical noteFunding Information:
This work was supported in part by NIH P30 CA77598 utilizing the following; Masonic Cancer Center, University of Minnesota Shared Resource: Genomic Engineering Shared Resource (GESR). This work was supported by NIH/NCI R01 CA192178 (to C.A. Lange) and the Tickle Family Land Grant Endowed Chair in Breast Cancer Research (held by C.A. Lange) and by an NIH/NCI F31 predoctoral fellowship (CA195877-01; to T.M. Regan Anderson), an NIH/NCI T32 training grant fellowship (CA009138; to T.M. Regan Anderson and C.P. Kerkvliet), and NIH/NCI R01 CA138488 (to T.N. Seagroves).