title: Phosphorylated ERalpha, HIF-1alpha, and MAPK signaling as predictors of primary endocrine treatment response and resistance in patients with breast cancer.
abstract: OBJECTIVE
  We aimed to identify signaling pathways involved in the response and resistance to aromatase inhibitor therapy in patients with breast cancer.
  
  
  METHODS
  One hundred fourteen women with T2-4 N0-1, estrogen receptor (ER) alpha-positive tumors were randomly assigned to neoadjuvant letrozole or letrozole plus metronomic cyclophosphamide. Twenty-four tumor proteins involved in apoptosis, cell survival, hypoxia, angiogenesis, growth factor, and hormone signaling were assessed by immunohistochemistry in pretreatment samples (eg, caspase 3, phospho- mammalian target of rapamycin, hypoxia-inducible factor 1alpha [HIF-1alpha], vascular endothelial growth factor, mitogen-activated protein kinase [MAPK], phosphorylated epidermal growth factor receptor, phosphorylated ERalpha [pERalpha]). A multivariate generalized linear regression approach was applied using a penalized least-square minimization to perform variable selection and regularization. Ten-fold cross-validation and iterative leave-one-out were employed to validate and test the model, respectively. Tumor size, nodal status, age, tumor grade, histological type, and treatment were included in the analysis.
  
  
  RESULTS
  Ninety-one patients (81%) attained a disease response, 48 achieved a complete clinical response (43%) whereas 22 did not respond (19%). Increased pERalpha and decreased p44/42 MAPK were significant factors for complete response to treatment in all leave-one-out iterations. Increased p44/42 MAPK and HIF-1alpha were significant factors for treatment resistance in all leave-one-out iterations. There was no significant interaction between these variables and treatment.
  
  
  CONCLUSIONS
  Activated ERalpha form was an independent factor for sensitivity to chemoendocrine treatment, whereas HIF-1alpha and p44/42 MAPK were independent factors for resistance. Although further confirmatory analyses are needed, these findings have clear potential implications for future strategies in the management of clinical trials with aromatase inhibitors in the breast cancer.
authors.affiliation: Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
authors.forename: Daniele
authors.initials: D
authors.lastname: Generali
authors.forename: Francesca M
authors.initials: FM
authors.lastname: Buffa
authors.forename: Alfredo
authors.initials: A
authors.lastname: Berruti
authors.forename: Maria P
authors.initials: MP
authors.lastname: Brizzi
authors.forename: Leticia
authors.initials: L
authors.lastname: Campo
authors.forename: Simone
authors.initials: S
authors.lastname: Bonardi
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bersiga
authors.forename: Giovanni
authors.initials: G
authors.lastname: Allevi
authors.forename: Manuela
authors.initials: M
authors.lastname: Milani
authors.forename: Sergio
authors.initials: S
authors.lastname: Aguggini
authors.forename: Mauro
authors.initials: M
authors.lastname: Papotti
authors.forename: Luigi
authors.initials: L
authors.lastname: Dogliotti
authors.forename: Alberto
authors.initials: A
authors.lastname: Bottini
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Fox
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D047072:Aromatase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D003520:Cyclophosphamide / Q000008:administration & dosage; D004334:Drug Administration Schedule; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D019394:Ki-67 Antigen / Q000378:metabolism; D000077289:Letrozole; D020935:MAP Kinase Signaling System; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020360:Neoadjuvant Therapy; D009570:Nitriles / Q000008:administration & dosage / Q000627:therapeutic use*; D010766:Phosphorylation; D014230:Triazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D000095043:Cyclin-Dependent Kinase-Activating Kinase
chemical_list: D047072:Aromatase Inhibitors; D047628:Estrogen Receptor alpha; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019394:Ki-67 Antigen; D009570:Nitriles; D014230:Triazoles; D000077289:Letrozole; D003520:Cyclophosphamide; D018844:Cyclin-Dependent Kinases; D048052:Mitogen-Activated Protein Kinase 3; D000095043:Cyclin-Dependent Kinase-Activating Kinase