ERa-mediated nuclear sequestration of RSK2 is required for ER þ breast cancer tumorigenesis

Katarzyna A. Ludwik, Oliver G. McDonald, David R. Brenin, Deborah A. Lannigan

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


Although ribosomal protein S6 kinase A3 (RSK2) activation status positively correlates with patient responses to antiestrogen hormonal therapies, the mechanistic basis for these observations is unknown. Using multiple in vitro and in vivo models of estrogen receptor–positive (ER þ ) breast cancer, we report that ERa sequesters active RSK2 into the nucleus to promote neoplastic transformation and facilitate metastatic tumor growth. RSK2 physically interacted with ERa through its N terminus to activate a proneoplastic transcriptional network critical to the ER þ lineage in the mammary gland, thereby providing a gene signature that effectively stratified patient tumors according to ERa status. ER þ tumor growth was strongly dependent on nuclear RSK2, and transgenic mice engineered to stably express nuclear RSK2 in the mammary gland developed high-grade ductal carcinoma in situ. Mammary cells isolated from the transgenic model and introduced systemically successfully disseminated and established metastatic lesions. Antiestrogens disrupted the interaction between RSK2 and ERa, driving RSK2 into the cytoplasm and impairing tumor formation. These findings establish RSK2 as an obligate participant of ERa-mediated transcriptional programs, tumorigenesis, and divergent patient responses to antiestrogen therapies. Significance: Nuclear accumulation of active RSK drives a pro-tumorigenic transcriptional program and renders ER þ breast cancer susceptible to endocrine-based therapies.

Original languageEnglish (US)
Pages (from-to)2014-2025
Number of pages12
JournalCancer Research
Issue number8
StatePublished - Apr 15 2018
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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