title: Oncogenic mechanisms ofHOXB13missense mutations in prostate carcinogenesis.
abstract: The recurrent germline mutationHOXB13p.(Gly84Glu) (G84E) has recently been identified as a risk factor for prostate cancer. In a recent study, we have performed full sequencing of theHOXB13gene in 462 Portuguese prostate cancer patients with early-onset and/or familial/hereditary disease, and identified two novel missense mutations, p.(Ala128Asp) (A128D) and p.(Phe240Leu) (F240L), that were predicted to be damaging to protein function. In the present work we aimed to investigate the potential oncogenic role of these mutations, comparing to that of the recurrent G84E mutation and wild-typeHOXB13. We induced site-directed mutagenesis in aHOXB13expression vector and establishedin vitrocell models of prostate carcinogenesis with stable overexpression of either the wild-type or the mutatedHOXB13variants. By performingin vitroassays we observed that, while the wild-type promotes proliferation, also observed with the F240L variant along with a decrease in apoptosis, the A128D mutation decreases apoptosis and promotes anchorage independent growth. No phenotypic impact was observed for the G84E mutation in the cell line model used. Our data show that specificHOXB13mutations are involved in the acquisition of different cancer-associated capabilities and further support an oncogenic role forHOXB13in prostate carcinogenesis.
authors.affiliation: Cancer Genetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), 4200-072 Porto, Portugal.
authors.forename: Marta
authors.initials: M
authors.lastname: Cardoso
authors.affiliation: Cancer Genetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), 4200-072 Porto, Portugal.
authors.forename: Sofia
authors.initials: S
authors.lastname: Maia
authors.affiliation: Cancer Genetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), 4200-072 Porto, Portugal.
authors.forename: Paula
authors.initials: P
authors.lastname: Paulo
authors.affiliation: Cancer Genetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), 4200-072 Porto, Portugal; Department of Genetics, Portuguese Oncology Institute of Porto (IPO Porto), 4200-072 Porto, Portugal; Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal.
authors.forename: Manuel R
authors.initials: MR
authors.lastname: Teixeira
keywords: HOXB13; germline mutations; in vitro assays; prostate cancer