Steroid receptors as MAPK signaling sensors in breast cancer: Let the fates decide

Research output: Contribution to journalReview articlepeer-review

4 Scopus citations

Abstract

Steroid hormone receptors (SRs) are classically defined as ligand-activated transcription factors that function as master regulators of gene programs important for a wide range of processes governing adult physiology, development, and cell or tissue homeostasis. A second function of SRs includes the ability to activate cytoplasmic signaling pathways. Estrogen (ER), androgen (AR), and progesterone (PR) receptors bind directly to membrane-associated signaling molecules including mitogenic protein kinases (i.e. c-SRC and AKT), G-proteins, and ion channels to mediate context-dependent actions via rapid activation of downstream signaling pathways. In addition to making direct contact with diverse signaling molecules, SRs are further fully integrated with signaling pathways by virtue of their N-terminal phosphorylation sites that act as regulatory hot-spots capable of sensing the signaling milieu. In particular, ER, AR, PR, and closely related glucocorticoid receptors (GR) share the property of accepting (i.e. sensing) ligand-independent phosphorylation events by proline-directed kinases in the MAPK and CDK families. These signaling inputs act as a ‘second ligand’ that dramatically impacts cell fate. In the face of drugs that reliably target SR ligand-binding domains to block uncontrolled cancer growth, ligand-independent post-translational modifications guide changes in cell fate that confer increased survival, EMT, migration/invasion, stemness properties, and therapy resistance of non-proliferating SR+ cancer cell subpopulations. The focus of this review is on MAPK pathways in the regulation of SR+ cancer cell fate. MAPK-dependent phosphorylation of PR (Ser294) and GR (Ser134) will primarily be discussed in light of the need to target changes in breast cancer cell fate as part of modernized combination therapies.

Original languageEnglish (US)
Pages (from-to)T35-T48
JournalJournal of molecular endocrinology
Volume65
Issue number1
DOIs
StatePublished - 2020

Bibliographical note

Funding Information:
This work was supported by NIH grants R01CA236948 (C A L and J H O), R01 CA159712 (C A L), F32 CA210340 (T H T), T32 HL007741 (T H T), and NIH?s National Center for Advancing Translational Sciences, grant UL1TR002494 (A R D). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health?s National Center for Advancing Translational Sciences. The Tickle Family Land Grant Endowed Chair in Breast Cancer Research (C A L) also supported this work.

Funding Information:
This work was supported by N 阀H grants R01CA236948 (C A L and J H O), R01 CA159712 (C A L), F32 CA210340 (T H T), T32 HL007741 (T H T), and N 阀H’s National Center for Advancing Translational Sciences, grant UL1TR002494 (A R D). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National 阀nstitutes of Health’s National Center for Advancing Translational Sciences. The Tickle Family Land Grant Endowed Chair in Breast Cancer Research (C A L) also supported this work.

Publisher Copyright:
© 2020 Society for Endocrinology.

Keywords

  • Breast cancer
  • Cancer stem cells
  • Glucocorticoid receptors
  • Map kinases
  • Progesterone receptors

PubMed: MeSH publication types

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

Fingerprint

Dive into the research topics of 'Steroid receptors as MAPK signaling sensors in breast cancer: Let the fates decide'. Together they form a unique fingerprint.

Cite this