Canine genetics offers new mechanisms for the study of human cancer.

In this month’s CEBP , Antuofermo et al. (1) offer new insights into spontaneous intraepithelial lesions using the dog as a discovery tool. In humans, f500,000 intraepithelial lesions are diagnosed every year, generally through mammographic screening (2). Intraepithelial lesions include breast hyperplasias, atypical hyperplasias, and carcinoma in situ, and all are considered risk factors for invasive breast cancer (3, 4). Thus, establishing an animal model for intraepithelial lesions is important for the development of both preventive measures and effective treatments and for better understanding of the etiology of the disease. Using data from 200 dogs, Antuofermo et al. (1) describe both the histologic and immunohistochemistry of canine intraepithelial lesions, showing their similarity to human lesions. Of the 200 canine specimens considered, 93 benign and 119 malignant tumors were found, with intraepithelial lesions observed in 60 cases, 39 of which were associated with malignant tumors. Ductal carcinoma in situ was the most common intraepithelial lesion found in dogs, accounting for 32 cases, 29 (91%) of which were associated with malignant tumors. Ductal carcinoma in situ is also the most frequently diagnosed intraepithelial lesion in humans. Estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 in adjacent nonneoplastic mammary tissue were evaluated by immunohistochemistry. Seventy percent of cells showed strong estrogen receptor immunoreactivity, with most ductal hyperplasias expressing estrogen receptor, which decreased as intraepithelial lesions increased in grade. In contrast, high-grade ductal carcinoma in situ was generally estrogen receptor negative, suggesting that the canine intraepithelial lesions might be a good model for estrogen receptor–negative tumors. Ki67 measures were also conducted: in humans, Ki67 indices are usually associated with increased tumor grade and poor response to therapy (5). In the dog intraepithelial lesions, estrogen receptor and Ki67 were found to be inversely associated, as has previously been reported (6). In highly proliferative lesions with increased Ki67, estrogen receptor was negative, but human epidermal growth factor receptor 2 was usually positive with a distribution that was similar to that reported for human intraepithelial lesions (7). With 74 million dogs living in the United States (8), it is not surprising that man’s best friend would emerge as an informative system for the study of precancerous lesions (9). Dogs live in our environment, eat our food, are exposed to the same carcinogens (10), and share similar immunologic features (11). Cancer is at least as common in dogs as in humans. In a necropsy series of 2,000 dogs, 23% of all dogs and 45% of dogs older than 10 years died of cancer (12, 13). The spontaneous appearance, frequency, and treatment response of canine tumors often parallel human neoplasms (14-16) much better than, for instance, induced tumors in rodents. Canine malignancies that have been established as strong comparative models (17) for human cancers include transitional cell carcinoma of the bladder (17), non-Hodgkin’s lymphoma (18, 19) and leukemia, osteosarcoma (20), melanoma (particularly oral melanoma; refs. 21, 22), and soft tissue sarcomas (23-25). In dogs, hormonal cancers display interesting epidemiologic patterns. Although prostate cancer is among the most common cancers in men with 218,890 estimated new cases in 2007 (26), it is rare in dogs (27). Further, although high-grade prostate intraepithelial neoplasia (28) and bone metastasis similar to those observed in humans have been reported (29), the significance of those results is unclear (30). Some breeds of dog seem to be at a higher risk for the disease, such as the Bouvier de Flanders, Doberman pinschers, Shetland sheepdogs, and the Norwegian Elkhound; the strongest risk factor is castration (27, 31). This is the opposite of what is observed in humans, in which prostate cancer is virtually undiagnosed in castrated males (32, 33). By comparison, the mammary gland is a common site of neoplasia in female dogs (12). Annual incidence rates are difficult to assess because most of the available data come from insurance databases in which younger dogs are overrepresented. Dobson et al. (34) estimated that the standardized incidence rate was 205 per 100,000 dogs per year. This is similar to the estimate of 145 per 100,000 female dogs per year reported by Schneider (35). The study of Schneider represents dogs from the Alameda Country Tumor Registry and Alameda Costa Counties Animal Neoplasm Registry, both of which include dogs of all ages. The median age at diagnosis for breast cancer in the Registry study was 11 years and