Stress sensing within the breast tumor microenvironment: how glucocorticoid receptors live in the moment

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6 Scopus citations


The classification and treatment of breast cancer is largely defined by the expression of steroid hormone receptors (HRs), namely estrogen receptor (ER) and progesterone receptor (PR), and gene amplification/overexpression of human epidermal growth factor receptor 2 (HER2). More recently, studies of androgen receptor (AR), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR) have revealed that targeting these related HRs may be a promising strategy for a more personalized approach to the treatment of specific subtypes of HR+ breast cancer. For example, GR expression is associated with a good prognosis in ER+ breast cancer, but predicts poor prognosis in triple-negative breast cancer (TNBC). GR, like ER, PRs, and AR, is a ligand-activated transcription factor, but also has significant ligand-independent signaling activities. GR transcriptional activity is classically regulated by circulating glucocorticoids (GCs; ligand-dependent). Recent studies demonstrate that GR transcriptional activity is also regulated by a variety of cellular stress stimuli that input to GR Ser134 phosphorylation via rapid activation of the p38 mitogen activated protein kinase (MAPK) signaling pathway (ligand-independent). Furthermore, ligand-independent GR activation promotes feedforward signaling loops that mediate sustained activation of stress signaling pathways to drive advanced cancer biology (i.e. migration, invasion, chemoresistance, survival, and cellular growth). In this review, we will focus on the role of GR as a key sensor and mediator of physiologic and tumor microenvironment (TME)-derived cellular stress signaling in TNBC and discuss how targeting GR and/or associated signaling pathways may provide a strategy to inhibit deadly TNBC progression.

Original languageEnglish (US)
Pages (from-to)971-983
Number of pages13
JournalEssays in Biochemistry
Issue number6
Early online dateJun 16 2021
StatePublished - Nov 2021

Bibliographical note

Funding Information:
This work was supported by the NIH [grant numbers R01 CA236948 (to Julie H. Ostrander and Carol A. Lange), R01CA192178 (to Carol A. Lange), T32CA009138 (to Carol A. Lange and Carlos Perez Kerkvliet), F30CA228261 (to Carlos Perez Kerkvliet)]; Employed and Received Compensation from the University of Minnesota (to Carol A. Lange, Julie H. Ostrander, and Thu H. Truong); M.D./Ph.D. student receiving a stipend from the University of Minnesota (to Carlos Perez Kerkvliet); and the Scientific Advisory Board Member for Context Therapeutics, Inc. (to Carol A. Lange).

Publisher Copyright:
© 2021 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review


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