title: Aurora-A mitotic kinase induces endocrine resistance through down-regulation of ERα expression in initially ERα+ breast cancer cells.
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.
authors.affiliation: Department of Medical Oncology, Mayo Clinic College Of Medicine, Rochester, Minnesota, United States of America.
authors.forename: Mateusz
authors.initials: M
authors.lastname: Opyrchal
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College Of Medicine, Rochester, Minnesota, United States of America.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Salisbury
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College Of Medicine, Rochester, Minnesota, United States of America.
authors.forename: Shuya
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Microbiology and Immunology, East Carolina University, Greenville, North Carolina, United States of America.
authors.forename: James
authors.initials: J
authors.lastname: McCubrey
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College Of Medicine, Rochester, Minnesota, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Hawse
authors.affiliation: Department of Medical Oncology, Mayo Clinic College Of Medicine, Rochester, Minnesota, United States of America.
authors.forename: Mattew P
authors.initials: MP
authors.lastname: Goetz
authors.affiliation: Department of Medical Oncology, Mayo Clinic College Of Medicine, Rochester, Minnesota, United States of America.
authors.forename: Gwen A
authors.initials: GA
authors.lastname: Lomberk
authors.affiliation: Department of Medical Oncology, Mayo Clinic College Of Medicine, Rochester, Minnesota, United States of America.
authors.forename: Tufia
authors.initials: T
authors.lastname: Haddad
authors.affiliation: Department of General Surgery, Mayo Clinic College Of Medicine, Rochester, Minnesota, United States of America.
authors.forename: Amy
authors.initials: A
authors.lastname: Degnim
authors.affiliation: Departments of Medicine and Pharmacology, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Carol
authors.initials: C
authors.lastname: Lange
authors.affiliation: Department of Medical Oncology, Mayo Clinic College Of Medicine, Rochester, Minnesota, United States of America.
authors.forename: James N
authors.initials: JN
authors.lastname: Ingle
authors.affiliation: Department of Medical Oncology, Mayo Clinic College Of Medicine, Rochester, Minnesota, United States of America; Department of Molecular Medicine, Mayo Clinic College Of Medicine, Rochester, Minnesota, United States of America.
authors.forename: Evanthia
authors.initials: E
authors.lastname: Galanis
authors.affiliation: Department of Medical Oncology, Mayo Clinic College Of Medicine, Rochester, Minnesota, United States of America; Department of Biochemistry and Molecular Biology, Mayo Clinic College Of Medicine, Rochester, Minnesota, United States of America.
authors.forename: Antonino B
authors.initials: AB
authors.lastname: D'Assoro
mesh_terms: D000818:Animals; D064096:Aurora Kinase A / Q000378:metabolism*; D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D018450:Disease Progression; D015536:Down-Regulation / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D006728:Hormones / Q000494:pharmacology*; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D051902:Smad5 Protein / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D006728:Hormones; D051902:Smad5 Protein; D064096:Aurora Kinase A