Glucocorticoid receptors orchestrate a convergence of host and cellular stress signals in triple negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that lacks expression of the nuclear steroid receptors that bind estrogens (ER) and progestogens (PRs) and does not exhibit HER2 (Human epidermal growth factor 2) receptor overexpression. Even in the face of initially effective chemotherapies, TNBC patients often relapse. One primary cause for therapy-resistant tumor progression is the activation of cellular stress signaling pathways. The glucocorticoid receptor (GR), a corticosteroid-activated transcription factor most closely related to PR, is a mediator of both endocrine/host stress and local tumor microenvironment (TME)-derived and cellular stress responses. Interestingly, GR expression is associated with a good prognosis in ER+ breast cancer but predicts poor prognosis in TNBC. Classically, GR's transcriptional activity is regulated by circulating glucocorticoids. Additionally, GR is regulated by ligand-independent signaling events. Notably, the stress-activated protein kinase, p38 MAP kinase, phosphorylates GR at serine 134 (Ser134) in response to TME-derived growth factors and cytokines, including HGF and TGFß1. Phospho-Ser134-GR (p-Ser134-GR) associates with cytoplasmic and nuclear signaling molecules, including 14-3-3ζ, aryl hydrocarbon receptors (AhR), and hypoxia-inducible factors (HIFs). Phospho-GR/HIF-containing transcriptional complexes upregulate gene sets whose protein products include the components of inducible oncogenic signaling pathways (PTK6) that further promote cancer cell survival, chemoresistance, altered metabolism, and migratory/invasive behavior in TNBC. Recent studies have implicated liganded p-Ser134-GR (p-GR) in dexamethasone-mediated upregulation of genes related to TNBC cell motility and dysregulated metabolism. Herein, we review the tumor-promoting roles of GR and discuss how both ligand-dependent and ligand-independent/stress signaling-driven inputs to p-GR converge to orchestrate metastatic TNBC progression.

Androgen receptor and estrogen receptor variants in prostate and breast cancers.

The androgen receptor (AR) and estrogen receptor alpha (ERα) are steroid receptor transcription factors with critical roles in the development and progression of prostate and breast cancers. Advances in the understanding of mechanisms underlying the ligand-dependent activation of these transcription factors have contributed to the development of small molecule inhibitors that block AR and ERα actions. These inhibitors include competitive antagonists and degraders that directly bind the ligand binding domains of these receptors, luteinizing hormone releasing hormone (LHRH) analogs that suppress gonadal synthesis of testosterone or estrogen, and drugs that block specific enzymes required for biosynthesis of testosterone or estrogen. However, resistance to these therapies is frequent, and is often driven by selection for tumor cells with alterations in the AR or ESR1 genes and/or alternatively spliced AR or ESR1 mRNAs that encode variant forms AR or ERα. While most investigations involving AR have been within the context of prostate cancer, and the majority of investigations involving ERα have been within the context of breast cancer, important roles for AR have been elucidated in breast cancer, and important roles for ERα have been elucidated in prostate cancer. Here, we will discuss the roles of AR and ERα in breast and prostate cancers, outline the effects of gene- and mRNA-level alterations in AR and ESR1 on progression of these diseases, and identify strategies that are being developed to target these alterations therapeutically.

Progesterone Receptor Signaling Promotes Cancer Associated Fibroblast Mediated Tumorigenicity in ER+ Breast Cancer.

Breast cancer progression involves intricate interactions between cancer cells and the tumor microenvironment (TME). This study elucidates the critical role of progesterone receptor (PR) signaling in mediating the protumorigenic effects of cancer-associated fibroblasts (CAFs) on estrogen receptor-positive (ER+) luminal breast cancer cells. We demonstrate that CAFs produce physiologically relevant levels of estrogen and progesterone, which significantly contribute to breast cancer tumorigenicity. Specifically, CAF conditioned media (CM) promoted PR-dependent anchorage-independent growth, tumorsphere formation/stem cell expansion, and CD44 upregulation. CAF cells formed co-clusters more frequently with PR+ breast cancer cells relative to PR-null models. While both PR isoforms mediated these actions, PR-A was a dominant driver of tumorsphere formation/stemness, while PR-B induced robust CD44 expression and CAF/tumor cell co-cluster formation. CD44 knockdown impaired CAF/tumor cell co-clustering. Fibroblast growth factor 2 (FGF2), also secreted by CAFs, phosphorylated PR (Ser294) in a MAPK-dependent manner and activated PR to enhance CD44 expression and breast cancer tumorigenicity. The FGF receptor (FGFR) inhibitor PD173074 diminished CAF- and FGF2-dependent PR activation, tumorsphere formation, and co-clustering. In summary, this study reveals a novel mechanism through which stromal CAFs orchestrate elevated PR signaling in ER+ luminal breast cancer via secretion of both progesterone and FGF2, a potent activator of ERK1/2. Understanding tumor cell/TME interactions provides insights into potential therapeutic strategies aimed at disrupting PR- and/or FGF2/FGFR-dependent signaling pathways to prevent early metastasis in patients with ER+ breast cancer.