Loss of Rad51c accelerates tumourigenesis in sebaceous glands of Trp53‐mutant mice. Issue 1 (January 2015)

• Record Type: Journal Article
• Authors: Tumiati, Manuela; Hemmes, Annabrita; Uusivirta, Sanna; Koopal, Sonja; Kankainen, Matti; Lehtonen, Eero; Kuznetsov, Sergey G
• Is Part Of: Journal of pathology. Volume 235:Issue 1(2015)
• Page Start: 136
• Page End: 146
• Publication Date: 2015-01
• Subjects: Pathology -- Periodicals; 616.07
• DOI: 10.1002/path.4455
• Languages: English
• ISSNs: 0022-3417

Abstract

<abstract abstract-type="main" id="path4455-abs-0001"> <title>Abstract</title> <p id="path4455-para-0001">Germline mutations in <italic>RAD51C</italic> predispose to breast and ovarian cancers. However, the mechanism of <italic>RAD51C</italic>‐mediated carcinogenesis is poorly understood. We previously reported a first‐generation <italic>Rad51c</italic>‐knock‐out mouse model, in which a spontaneous loss of both <italic>Rad51c</italic> and <italic>Trp53</italic> together resulted in a high incidence of sebaceous carcinomas, particularly in preputial glands. Here we describe a second‐generation mouse model, in which <italic>Rad51c</italic> is deleted, alone or together with <italic>Trp53</italic>, in sebaceous glands, using Cre‐mediated recombination. We demonstrate that deletion of <italic>Rad51c</italic> alone is not sufficient to drive tumourigenesis and may only cause keratinization of preputial sebocytes. However, deletion of <italic>Rad51c</italic> together with <italic>Trp53</italic> leads to tumour development at around 6 months of age, compared to 11 months for single <italic>Trp53</italic>‐mutant mice. Preputial glands of double‐mutant mice are also characterized by increased levels of cell proliferation and DNA damage and form multiple hyperplasias, detectable as early as 2 months of age. Our results reveal a critical synergy between <italic>Rad51c</italic> and <italic>Trp53</italic> in tumour progression and provide a predictable <italic>in vivo</italic> model system for studying mechanisms of <italic>Rad51c</italic>‐mediated carcinogenesis. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.</p> </abstract>