title: Gender influences the class III and V β-tubulin ability to predict poor outcome in colorectal cancer.
abstract: OBJECTIVE
  Colorectal cancer is one of the deadliest diseases in Western countries. To predict the outcome of therapy, we assessed the role of class III (TUBB3) and class V β-tubulin (TUBB6) as predictive biomarkers.
  
  
  METHODS
  Using immunohistochemistry and nanofluidics, the expression of TUBB3 and TUBB6 was assessed in two cohorts of 180 and 134 patients, respectively. The CYP17A1 RS743572 was genotyped to identify GG carriers with enhanced androgen levels. TUBB3 and TUBB6 were investigated in 22 colorectal cancer cell lines in basal conditions and after serum starvation, the latter serving as activator of this prosurvival pathway. To ascertain the role of androgen receptor (AR) in such regulation, we silenced AR and checked TUBB3 and TUBB6 expression and sensitivity to chemotherapy.
  
  
  RESULTS
  There was a link between poor survival, the expression of TUBB3/TUBB6, and AR only in females. Conversely, only in males carriers of the GG phenotype exhibited the worst outcome. Importantly, male cell lines were resistant to serum starvation and exhibited higher levels of TUBB6, thereby suggesting that the pathway is activated by androgens. In female cells this phenomenon was absent. In both genders, AR was the main driver of TUBB3/TUBB6 expression, as constitutive silencing of AR was associated with downregulation of TUBB3/TUBB6 expression and increased sensitivity to oxaliplatin and SN-38.
  
  
  CONCLUSIONS
  The involvement of androgens in the TUBB3 pathway opens the way for clinical trials to assess the efficacy of antiandrogens for increasing the efficacy of chemotherapy in male colorectal cancer patients.
authors.affiliation: Danbury Hospital Research Institute, Danbury, Connecticut 00168, USA.
authors.forename: Marisa
authors.initials: M
authors.lastname: Mariani
authors.forename: Gian Franco
authors.initials: GF
authors.lastname: Zannoni
authors.forename: Stefano
authors.initials: S
authors.lastname: Sioletic
authors.forename: Steven
authors.initials: S
authors.lastname: Sieber
authors.forename: Candice
authors.initials: C
authors.lastname: Martino
authors.forename: Enrica
authors.initials: E
authors.lastname: Martinelli
authors.forename: Claudio
authors.initials: C
authors.lastname: Coco
authors.forename: Giovanni
authors.initials: G
authors.lastname: Scambia
authors.forename: Shohreh
authors.initials: S
authors.lastname: Shahabi
authors.forename: Cristiano
authors.initials: C
authors.lastname: Ferlini
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002166:Camptothecin / Q000031:analogs & derivatives / Q000627:therapeutic use; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000077146:Irinotecan; D008297:Male; D009944:Organoplatinum Compounds / Q000627:therapeutic use; D000077150:Oxaliplatin; D034622:RNA Interference; D034741:RNA, Small Interfering; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D012727:Sex Characteristics; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics; D016896:Treatment Outcome; D014404:Tubulin / Q000235:genetics / Q000378:metabolism*
chemical_list: C410798:AR protein, human; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D009944:Organoplatinum Compounds; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; C498585:TUBB3 protein, human; D014404:Tubulin; D000077150:Oxaliplatin; D000077146:Irinotecan; C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase; D002166:Camptothecin