Id Proteins Contribute to Tumor Development and Metastatic Colonization in a Model of Bladder Carcinogenesis

Background: Bladder cancer is one of the most common malignant genitourinary diseases worldwide. Despite advances in surgical technique, medical oncology and radiation therapy, cure of invasive tumors remains elusive for patients with late stage disease. Therefore, new therapeutic strategies are needed to improve the response rates with regard to recurrence, invasion and metastasis. Objective: Inhibitor of DNA binding (Id) proteins have been proposed as therapeutic targets due to the key regulatory role they exert in multiple steps of cancer. We aimed to explore the role of Id proteins in bladder cancer development and the pattern of expression of Id proteins in bladder carcinomas. Methods: We used a well-established chemically induced model of bladder carcinogenesis. Wild type and Id-deficient mice were given N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) in the drinking water and urinary bladder lesions were analyzed histopathologically and stained for Id1. We assessed the effects of Id1 inactivation in cultured bladder cancer cells and in a model of metastatic lung colonization. We also performed Id1 staining of human urothelial carcinoma samples and matched lymph node metastases. Results: Id1 protein was overexpressed in the BBN-induced model of bladder cancer. Id1 deficiency resulted in the development of urinary bladder tumors with areas of extensive hemorrhage and decreased invasiveness when compared to wild type mice. Id1 inactivation led to decreased cell growth in vitro and lung colonization in vivo of human bladder cancer cells. Immunohistochemistry performed on human urothelial carcinoma samples showed Id1 positive staining in both primary tumors and lymph node metastases. Conclusions: In summary, our studies reveal the physiological relevance of Id1 in bladder cancer progression and suggest that targeting Id1 may be important in the development of novel therapies for the treatment of bladder cancer.