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

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 ( = 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. Breast cancer cells enlist intracellular stress response pathways that evade chemotherapy by increasing cancer cell survival and promoting migratory phenotypes. .

PELP1/SRC-3-dependent regulation of metabolic kinases drives therapy resistant ER+ breast cancer

“…We observed similarities in gene expression, cell metabolism, and sensitivity to inhibitors of PELP1 binding partners in endocrine and chemotherapy resistant ER+ cell lines. Although PELP1 expression contributes to cell survival in response to Taxol in TNBC (14), our studies are the first to demonstrate enhanced Taxol tolerance in the context of cyto PELP1 in ER+ breast cancer. Our results in TaxR models highlight the impact of targeting PELP1 binding partners involved in PELP1-mediated CSC self-renewal (Figure 4).…”

“…Paclitaxel (Taxol) is a chemotherapy used to treat late stage breast cancer. Increased PELP1, HIF1α, and HIF-2α expression has been observed in triple negative breast cancer (TNBC) cells in response to Taxol (14). To evaluate whether PELP1 expression affects response to Taxol in ER+ breast cancer, we treated MCF-7 PELP1 cells (LXSN, WT PELP1, cyto PELP1) cultured as tumorspheres with Taxol (0 to 125 nM).…”

90 YEARS OF PROGESTERONE: Steroid receptors as MAPK signaling sensors in breast cancer: let the fates decide

“…However, activation of GR also promotes cell survival in a variety of epithelial cell types, including in breast cancer models. In studies of TNBC, liganddependent and ligand-independent GR activation have been shown to promote expression of pro-survival proteins (Wu et al 2004, Regan Anderson et al 2018. For example, GR promotes breast tumor kinase (Brk/PTK6) expression in response to dexamethasone (liganddependent), and also in response to hypoxia, cell stress induced by chemotherapy, and anoikis (ligandindependent).…”

“…For example, GR promotes breast tumor kinase (Brk/PTK6) expression in response to dexamethasone (liganddependent), and also in response to hypoxia, cell stress induced by chemotherapy, and anoikis (ligandindependent). In TNBC models, hypoxia, paclitaxel, 5-FU, and non-adherent culture all led to p38-MAPKdependent GR Ser134 phosphorylation and ligandindependent activation of gene programs implicated in cellular stress-response (Regan Anderson et al 2016Anderson et al , 2018. GR-dependent Brk/PTK6 induction protected cells from chemotherapy-induced cell death and promoted cell migration (Regan Anderson et al 2018).…”

“…While the extent to which phosphorylation events modify the GR cistrome is still being studied, such modifications significantly alter GR function (Galliher-Beckley et al 2011). For example, recent collaborative studies from our group (Regan Anderson et al 2016Anderson et al , 2018 have established GR as an important sensor of both life stress (i.e. a collection of classical GR ligands acting via the LBD) as well as inducible cellular (hypoxia, reactive oxygen species (ROS), nutrient starvation), and microenvironmental T37 65 1 : A R Dwyer, T H Truong et al…”