Aurora-A mitotic kinase induces endocrine resistance through down-regulation of ERα expression in initially ERα+ breast cancer cells

Mateusz Opyrchal, Jeffrey L. Salisbury, Shuya Zhang, James McCubrey, John Hawse, Mattew P. Goetz, Gwen A. Lomberk, Tufia Haddad, Amy Degnim, Carol Lange, James N. Ingle, Evanthia Galanis, Antonino B. D'Assoro

Research output: Contribution to journalArticle

14 Scopus citations


Development of endocrine resistance during tumor progression represents a major challenge in the management of estrogen receptor alpha (ERα) positive breast tumors and is an area under intense investigation. Although the underlying mechanisms are still poorly understood, many studies point towards the 'cross-talk' between ERα and MAPK signaling pathways as a key oncogenic axis responsible for the development of estrogen-independent growth of breast cancer cells that are initially ERα+ and hormone sensitive. In this study we employed a metastatic breast cancer xenograft model harboring constitutive activation of Raf-1 oncogenic signaling to investigate the mechanistic linkage between aberrant MAPK activity and development of endocrine resistance through abrogation of the ERα signaling axis. We demonstrate for the first time the causal role of the Aurora-A mitotic kinase in the development of endocrine resistance through activation of SMAD5 nuclear signaling and down-regulation of ERα expression in initially ERα+ breast cancer cells. This contribution is highly significant for the treatment of endocrine refractory breast carcinomas, because it may lead to the development of novel molecular therapies targeting the Aurora-A/SMAD5 oncogenic axis. We postulate such therapy to result in the selective eradication of endocrine resistant ERαlow/- cancer cells from the bulk tumor with consequent benefits for breast cancer patients.

Original languageEnglish (US)
Article numbere96995
JournalPloS one
Issue number5
StatePublished - May 9 2014


ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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