Human adenovirus type 9-induced rat mammary tumors

Abstract

Following subcutaneous inoculation of newborn Wistar-Furth rats with human adenovirus type 9 (Ad9), 16 of 16 female and 0 of 11 male rats developed mammary tumors. Tumor-positive animals usually developed tumors in multiple glands. Histopathological analyses indicated that three general categories of tumor could be identified. Mammary fibroadenomas were the most common tumor type encountered, but phyllodeslike tumors and solid sarcomas were also frequently found. In situ hybridization and immunohistochemical techniques established that benign fibroadenomas were derived from mammary fibroblasts (collagen type I-and vimentin-positive cells) and that malignant tumors were derived from myoepithelial cells (collagen type IV-, vimentin-, and muscle-specific actin-positive cells). The fact that mammary tumors were limited to female rats suggested that female hormones are essential for tumor growth and development. In this regard, ovariectomy of Ad9-infected female rats prevented tumor development, while subsequent diethylstilbestrol (DES) treatment elicited tumor formation. In addition, Ad9-infected and castrated male rats which received DES also developed mammary tumors. Established male mammary tumors regressed when DES treatment was stopped and reappeared after DES treatment was resumed. Together, these results indicate that estrogen is required for both initiation and maintenance of Ad9-induced mammary tumors. Southern blot analysis of high-molecularweight tumor DNA showed that mammary tumor cells contained single or multiple integrated copies of the entire Ad9 genome. RNase protection experiments established that estrogen receptor as well as Ad9 Ela and E4 mRNAs were expressed in mammary tumors, but Ad9 E3 and, surprisingly, Elb mRNAs were not expressed at detectable levels.

Human adenovirus type 9 E4 open reading frame 1 encodes a cytoplasmic transforming protein capable of increasing the oncogenicity of CREF cells

“…Human adenoviruses are classified as DNA tumor viruses by virtue of their ability to cause tumors when inoculated into rodents. Unlike other oncogenic adenoviruses, the subgroup D human adenovirus type 9 (Ad9) causes only estrogen-dependent mammary tumors in female rats (1,2,23). The prevailing mammary tumor produced in Ad9-infected rats is fibroadenoma, which is also the most common type of breast tumor encountered in young women (36).…”

Viral Disease

“…Mastadenoviruses have been detected in metagenomic analysis of feces, intestinal contents, and sera from wild Rattus norvegicus (Firth et al, 2014;Sachsenroder et al, 2014). Several models of human adenoviruseinduced diseases (adenovirus 12induced neuroepithelial tumors, adenovirus 9-induced mammary tumors, and adenovirus 36induced obesity) have been established in rats (Javier et al, 1991;Ogawa, 1989aOgawa, , 1989bPasarica et al, 2008).…”

Biology of Adenovirus and Its Use as a Vector for Gene Therapy

“…The E4 transcription unit encodes a number of proteins that have been known to play a role in cell cycle control and transformation; however, the mechanisms underlying these functions have remained unclear until recently. Early studies on the E4orf1 protein of Ad9 demonstrated that it is able to induce estrogen-dependent mammary tumors in mice (Javier et al, 1991). Interestingly, Ad9 E4orf1 can bind the candidate tumor suppressor ZO (zonula occludens) protein whereas the nononcogenic Ad5 E4orf1 cannot (Glaunsinger et al, 2001).…”