Alternative Splicing Programs in Prostate Cancer

Prostate cancer (PCa) remains one of the most frequent causes of death for cancer in the male population. Although the initial antiandrogenic therapies are efficacious, PCa often evolves into a hormone-resistant, incurable disease. The genetic and phenotypic heterogeneity of this type of cancer renders its diagnosis and cure particularly challenging. Mounting evidence indicates that alternative splicing, the process that allows production of multiple mRNA variants from each gene, contributes to the heterogeneity of the disease. Key genes for the biology of normal and neoplastic prostate cells, such as those encoding for the androgen receptor and cyclin D1, are alternatively spliced to yield protein isoforms with different or even opposing functions. This review illustrates some examples of genes whose alternative splicing regulation is relevant to PCa biology and discusses the possibility to exploit alternative splicing regulation as a novel tool for prognosis, diagnosis, and therapeutic approaches to PCa. 1. Introduction Cancer cells are characterized by uncontrolled growth and ability to migrate from the primary lesion and to establish metastases in distant tissues. Standard therapies involve surgical removal of the tumor mass, radiation, and chemotherapy, which exploit the increased growth rate of cancer cells with respect to surrounding cells. More targeted approaches have also been developed in the last decades by directly inhibiting the function of the oncoproteins responsible for the neoplastic transformation. Nevertheless, although many human cancers initially respond to therapies, and in some cases patients are cured, most of them are characterized by disease relapse that often occurs in more aggressive and incurable forms. In this regard, a clear example of aggressive relapsing tumor is represented by prostate carcinoma (PCa), which remains one of the main causes of death for cancer in the male population [1, 2]. Understanding the mechanisms that lead to the acquisition of resistance to therapies in PCa patients might offer new molecular markers for earlier and more accurate diagnoses. Furthermore, identification of the key players involved in the transition to therapy-refractory stages may shed light on new targets for pharmaceutical intervention and open the path for the development of novel and more efficacious therapies. PCa cells rely on androgens and on the androgen receptor (AR) for proliferation [1]. Under normal conditions, the AR is localized in the cytoplasm; upon binding to androgens, the receptor dimerizes, translocates to the