HMGA2 expression in a canine model of prostate cancer

Abstract

Prostate cancer is the most prevalent cancer in western countries, being the third leading cause of male cancer death. To check its possible significance as a prognostic marker, allowing a better prognosis of the tumor, we analyzed the high-mobility group protein-A2 gene (HMGA2) expression level because HMGA2 overexpression has been shown to correlate with the malignant potential of various neoplasias. Aside from man, the dog is the only mammalian species that shows spontaneously occurring prostate carcinoma with striking similarities to prostate cancer growth and progression in man, making it an adequate animal model for this neoplasia. We used real-time quantitative reverse-transcription polymerase chain reaction for HMGA2 expression analyses in a subset of canine prostate tissue samples. Our investigations reveal that HMGA2 expression levels in all carcinomas were higher than those of any of the nonmalignant tissues. Thus, canine prostate cancer represents a spontaneously occurring model to test therapeutic effects resulting from reduced expression of HMGA2.

Introduction

According to a recent study of the World Health Organization (WHO), prostate cancer is the most prevalent cancer in western countries and is the third leading cause of male cancer death [1]. Prostate cancer most commonly affects men over the age of 50 years. Thus, considering the worldwide trend towards an aging population, the number of prostate cancer deaths can be expected to increase. There have been 220,900 new prostate cancer cases in the United States in 2003, increasing to 234,460 new prostate cancer cases in the United States in 2006. By the year 2020, 393,000 prostate cancer-related deaths are expected worldwide [1], [2], [3]. Therefore, research into that tumor is a major challenge for future management of the disease. Of particular relevance are parameters allowing a better prediction of the course of the disease, because based on the histology of the lesions alone, it is often not possible to sufficiently recognize the malignant potential of the tumor in terms of local invasiveness and metastatic spread. Nevertheless, the latter is a prerequisite for appropriate therapy management. Even more challenging is the field of “theragnostics.” To address these questions, animal models are of valuable help. Of these, the dog will be increasingly important in the future.

Besides humans, the dog is the only mammalian species that spontaneously develops prostate cancer with a considerably high frequency [4]. In addition, both species show striking similarities in the development and clinical course of the disease. The average age in which prostate carcinomas appear in dogs is 10 years, closely resembling the situation in men, where prostate carcinoma most commonly appears in older patients [1], [2], [5]. In both species, adenocarcinomas of the prostate represent a locally invasive disease. The tumors also tend to metastasize to the same distant regions in both species [6], and akin to their human counterparts, canine prostatic cancers vary over a broad range with respect to their clinical behavior. There currently is no widely accepted grading system for canine prostate cancer.

In human prostate carcinomas, overexpression of HMGA1 has been described to correlate with more aggressive disease [7]. The similar protein HMGA2 is encoded by a separate gene mapping to 12q14∼q15 [8]. All HMGA proteins show a high amino acid sequence homology, particularly among their three highly conserved AT hooks, representing the DNA-binding domains [9]. HMGA proteins are abundantly expressed during embryogenesis and expressed at very low levels in most normal adult tissues [10], [11]. HMGA2, however, is frequently involved in chromosomal translocations occurring in benign human tumors, such as lipomas, uterine leiomyomas, lung hamartomas, and fibroadenomas and adenolipomas of the breast [12], [13], [14], [15], [16], [17], [18]. It has been demonstrated that truncated transcripts are able to induce cell transformation [19]. The present study addresses the potential role of HMGA2 expression in canine prostate tumors and non-malignant tissues because the dog is the only animal model with spontaneously occurring prostate cancers. If overexpression of HMGA2 plays a role in these tumors, canines would constitute a suitable model to study the therapeutic effects aimed at a reduced expression of HMGA2.