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Aurora-A mitotic kinase induces endocrine resistance through down-regulation of ERα expression in initially ERα+ breast cancer cells. PLoS One 2014;9(5):e96995

Date

05/13/2014

Pubmed ID

24816249

Pubmed Central ID

PMC4016211

DOI

10.1371/journal.pone.0096995

Scopus ID

2-s2.0-84901235407 (requires institutional sign-in at Scopus site)   28 Citations

Abstract

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.

Author List

Opyrchal M, Salisbury JL, Zhang S, McCubrey J, Hawse J, Goetz MP, Lomberk GA, Haddad T, Degnim A, Lange C, Ingle JN, Galanis E, D'Assoro AB

Author

Gwen Lomberk PhD Professor in the Surgery department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Aurora Kinase A
Breast Neoplasms
Disease Progression
Down-Regulation
Drug Resistance, Neoplasm
Estrogen Receptor alpha
Female
Hormones
Humans
MCF-7 Cells
Mice
Smad5 Protein
Xenograft Model Antitumor Assays