Progesterone Receptor Scaffolding Function in Breast Cancer

Abstract

Progesterone receptors (PR) are critical mediators of mammary gland development and contribute to breast cancer progression. Progestin-induced rapid activation of cytoplasmic protein kinases leads to selective regulation of growth-promoting genes by phospho-PR species. We have shown that phosphorylation of PR Ser81 is ck2-dependent and progestin-regulated in intact cells. Mutation of the CD domain in PR (mCD PR) abrogates phosphorylation on Ser81, indicating that the CD domain in necessary to facilitate phosphorylation at this site (Ser81). T47D breast cancer cells stably expressing a PR-B mutant that cannot be phosphorylated at Ser81 (S81A) formed fewer soft agar colonies under ligand-independent conditions. Regulation of selected genes by PR-B also required Ser81 phosphorylation for basal and/or progestin-regulated (BIRC3, HSD11 beta 2, and HbEGF) expression. We conclude that phospho-Ser81 PR provides a platform for ck2 recruitment and regulation of selected PR-B target genes. Understanding how mitogenic protein kinases, such as ck2, alter PR phosphorylation and function is critical to fully understanding breast tumor etiology and developing better targeted therapies. Recent clinical data linking the progesterone component of hormone-replacement therapy regimens with the development of breast cancer underscores the importance of understanding how PR works in the context of breast cancer and high kinase environments. Due to the ubiquitous nature of ck2 and its prevalence in many different types of cancer, there has been much interest in the development of ck2 inhibitors as anti-cancer agents. Clinical ck2 inhibitors, in combination with more specific anti-progestins (new classes of selective progesterone receptor modulators or SPRMs), could provide an effective combination of targeted therapy for breast cancer treatment.

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Document Details

Document Type
Technical Report
Publication Date
Oct 28, 2010
Accession Number
ADA538856

Entities

People

  • Christy R Hagan

Organizations

  • University of Minnesota

Tags

DTIC Thesaurus Topics

  • Breast Cancer
  • Cancer
  • Cell Line
  • Cell Physiological Processes
  • Cells
  • Chemical Synthesis
  • Chemistry
  • Culture Media
  • Drug Therapy
  • Epithelial Cells
  • Gene Therapy
  • Genetics
  • Hormones
  • Neoplasms
  • Peptide Growth Factors
  • Proteins
  • Tumor Cell Line

Fields of Study

  • Biology

Readers

  • Breast cancer cell signaling and growth regulation.
  • Molecular and Cellular Biochemistry