MSK1 regulates luminal cell differentiation and metastatic dormancy in ER+ breast cancer

Nat Cell Biol. 2018 Feb;20(2):211-221. doi: 10.1038/s41556-017-0021-z. Epub 2018 Jan 22.

Abstract

For many patients with breast cancer, symptomatic bone metastases appear after years of latency. How micrometastatic lesions remain dormant and undetectable before initiating colonization is unclear. Here, we describe a mechanism involved in bone metastatic latency of oestrogen receptor-positive (ER+) breast cancer. Using an in vivo genome-wide short hairpin RNA screening, we identified the kinase MSK1 as an important regulator of metastatic dormancy in breast cancer. In patients with ER+ breast cancer, low MSK1 expression associates with early metastasis. We show that MSK1 downregulation impairs the differentiation of breast cancer cells, increasing their bone homing and growth capacities. MSK1 controls the expression of genes required for luminal cell differentiation, including the GATA3 and FOXA1 transcription factors, by modulating their promoter chromatin status. Our results indicate that MSK1 prevents metastatic progression of ER+ breast cancer, suggesting that stratifying patients with breast cancer as high or low risk for early relapse based on MSK1 expression could improve prognosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Biomarkers, Tumor / genetics
  • Bone Neoplasms / genetics
  • Bone Neoplasms / pathology
  • Bone Neoplasms / secondary
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Cell Differentiation / genetics
  • Chromatin / genetics
  • Female
  • GATA3 Transcription Factor / genetics*
  • Gene Expression Regulation, Neoplastic
  • Genome, Human / genetics
  • Hepatocyte Nuclear Factor 3-alpha / genetics*
  • Humans
  • Mice
  • Middle Aged
  • Neoplasm Metastasis
  • Prognosis
  • RNA, Small Interfering / genetics
  • Receptors, Estrogen / genetics
  • Ribosomal Protein S6 Kinases, 90-kDa / genetics*
  • Xenograft Model Antitumor Assays

Substances

  • Biomarkers, Tumor
  • Chromatin
  • FOXA1 protein, human
  • GATA3 Transcription Factor
  • GATA3 protein, human
  • Hepatocyte Nuclear Factor 3-alpha
  • RNA, Small Interfering
  • Receptors, Estrogen
  • Ribosomal Protein S6 Kinases, 90-kDa
  • mitogen and stress-activated protein kinase 1