Abstract
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. 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. 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. 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.
Highlights
Colorectal cancer is one of the deadliest diseases known in Western countries [1]
There was a link between poor survival, the expression of TUBB3/TUBB6, and androgen receptor (AR) only in females
Male cell lines were resistant to serum starvation and exhibited higher levels of TUBB6, thereby suggesting that the pathway is activated by androgens
Summary
Colorectal cancer is one of the deadliest diseases known in Western countries [1]. Its incidence in the United States is about 140,000 novel cases per year, and it is the third leading cause of cancer-related deaths when men and women are considered separately, second when both genders are combined. It is estimated to have caused about 51,370 deaths (26,580 in men and 24,790 in women) during 2010. The number of deaths has gone down in the last 2 decades, including the wider use of early surgery and endoscopic techniques combined with screening campaigns, there is an urgent need to improve outcomes for those patients who are diagnosed at an advanced stage. Authors' Affiliations: 1Danbury Hospital Research Institute, Danbury, Connecticut; 2Department of Oncology, Catholic University of the Sacred Heart, Campobasso; 3Department of Pathology, Catholic University of the Sacred Heart; and 4General Surgery Unit, Complesso Integrato Columbus, Catholic University of the Sacred Heart, Rome, Italy
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