title: Reversal of endocrine resistance in breast cancer: interrelationships among 14-3-3ζ, FOXM1, and a gene signature associated with mitosis.
abstract: BACKGROUND
  Despite the benefits of estrogen receptor (ER)-targeted endocrine therapies in breast cancer, many tumors develop resistance. 14-3-3 ζ/YWHAZ, a member of the 14-3-3 family of conserved proteins, is over-expressed in several types of cancer, and our previous work showed that high expression of 14-3-3ζ in ER-positive breast cancers was associated with a poor clinical outcome for women on tamoxifen. Therefore, we now probe the role of 14-3-3ζ in endocrine resistance, and we examine the functional dimensions and molecular basis that underlie 14-3-3ζ activities.
  
  
  METHODS
  From analyses of four independent breast cancer microarray datasets from nearly 400 women, we characterized a gene signature that correlated strongly with high expression of 14-3-3ζ in breast tumors and examined its association with breast cancer molecular subtypes and clinical-pathological features. We investigated the effects of altering 14-3-3ζ levels in ER-positive, endocrine sensitive and resistant breast cancer cells on the regulation of 14-3-3ζ signature genes, and on cellular signaling pathways and cell phenotypic properties.
  
  
  RESULTS
  The gene signature associated with high 14-3-3ζ levels in breast tumors encompassed many with functions in mitosis and cytokinesis, including aurora kinase-B, polo-like kinase-1, CDC25B, and BIRC5/survivin. The gene signature correlated with early recurrence and risk of metastasis, and was found predominantly in luminal B breast cancers, the more aggressive ER-positive molecular subtype. The expression of the signature genes was significantly decreased or increased upon reduction or overexpression of 14-3-3ζ in ER-positive breast cancer cells, indicating their coregulation. 14-3-3ζ also played a critical role in the regulation of FOXM1, with 14-3-3ζ acting upstream of FOXM1 to regulate cell division-signature genes. Depletion of 14-3-3ζ markedly increased apoptosis, reduced proliferation and receptor tyrosine kinase (HER2 and EGFR) signaling, and, importantly, reversed endocrine resistance.
  
  
  CONCLUSIONS
  This study reveals that 14-3-3ζ is a key predictive marker for risk of failure on endocrine therapy and serves a pivotal role impacting growth factor signaling, and promoting cell survival and resistance to endocrine therapies. Targeting 14-3-3ζ and its coregulated proteins, such as FOXM1, should prove valuable in restoring endocrine sensitivity and reducing risk of breast cancer recurrence.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois and College of Medicine at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Bergamaschi
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Christensen
authors.forename: Benita S
authors.initials: BS
authors.lastname: Katzenellenbogen
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D005260:Female; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics*; D015870:Gene Expression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D053208:Kaplan-Meier Estimate; D008938:Mitosis / Q000235:genetics*; D020033:Protein Isoforms / Q000235:genetics; D011960:Receptors, Estrogen / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D048948:14-3-3 Proteins; D018931:Antineoplastic Agents, Hormonal; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D020033:Protein Isoforms; D011960:Receptors, Estrogen; D013629:Tamoxifen