Although hormone-targeting strategies have been a mainstay of prostate and breast cancer therapies for decades, an improved understanding of the mechanisms underlying these malignancies has led researchers to focus fresh attention on the complex activity of the androgen receptor (AR) as a point of attack.
It has long been appreciated that prostate cancer is an androgen-driven disease, but androgen deprivation therapies aimed at reducing the levels of circulating androgens have no effect in castration- resistant prostate cancer (CRPC). In recent years, it has become clear that androgens and androgen- driven signaling through the AR are important not only for development of prostate cancer but also as a driving force in the development of CRPC.
The outlook for patients with CRPC is beginning to brighten as a result of the development of more rationally designed AR-targeting therapies based on our improved understanding of the biology of this disease.
In breast cancer, researchers have attempted to unravel the role that androgens play in promoting tumors since the early 20th century, but the success of estrogen-targeting agents pushed such inquiries to the side.
The advent of genomic profiling has opened a new window into the AR in breast cancer, resulting in attempts to determine whether drugs developed for the treatment of prostate cancer can also help individuals with breast cancer, particularly triple-negative breast cancer (TNBC).
AR Signaling Networks
Many cellular processes are activated in AR signaling, with the MAPK and PI3K-Akt pathways, illustrated at right, among the best characterized networks. The process of androgen metabolism through testosterone is shown at left.
AR indicates androgen receptor; ARE, androgen response elements; PIP, phosphatidylinositol phosphate; DHEA, dehydroepiandrosterone; DHT, dihydrotestosterone; hsp, heat shock protein; P, phosphorylation. Adapted from Girling JS et al. Pathogenesis of prostate cancer and hormone refractory prostate cancer. Indian J Urol. 2007;23(1):35-42.
A Driving Force for Prostate Cancer
The AR is a member of the nuclear steroid hormone family that also includes the progesterone receptor (PR) and the estrogen receptor (ER). It is responsible for mediating the effects of male hormones, known as androgens, which are synthesized primarily by the testes and play an important role in the development and maintenance of the male reproductive tissues.
Predominantly found in an inactive state in the cytoplasm in a complex with other proteins, including heat-shock proteins (HSPs), the AR is activated upon binding of androgens in target tissues, including the prostate. The main androgens in humans are testosterone and its more active metabolite, 5-alpha-dihydrotestosterone (DHT).
Binding of androgens frees the AR from its protein complex and allows it to move into the nucleus where it acts as a transcription factor, binding to target genes through androgen response elements.
Many of the genes targeted by the AR are involved in the growth and survival of prostate cancer cells; therefore, dysregulation of AR activity is strongly implicated in prostate cancer development. Indeed, around 15% of the mutations identified in the AR to date have been shown to be responsible for increased predisposition to prostate cancer in males.
Preventing Androgen-Stimulated Growth
Since prostate cancer is an androgen-driven disease, treatment strategies have focused on finding ways to lower circulating androgen levels. An effective way to achieve this is via castration, either surgically (by removal of the testes) or chemically (through the use of gonadotropin-releasing hormone [GnRH] agonists and antagonists). GnRH regulates synthesis of testosterone in the testes; antagonists reduce testosterone levels directly, while agonists cause an initial increase followed by a huge decrease.
Since testosterone can be synthesized elsewhere in the body (eg, adrenal glands) neither surgical nor chemical castration are completely effective at reducing circulating androgen levels. An alternative form of androgen-deprivation therapy (ADT) involves the use of antiandrogens, drugs that block the body’s ability to use androgens.
While these treatments have become standard of care for patients with prostate cancer, they do not currently provide a cure and the disease inevitably progresses to CRPC.
An Unexpected Role in CRPC
CRPC is a clinical state in which the tumor grows in spite of reduced levels of testosterone induced by the treatment options discussed above. Initially, it was believed that prostate cancer cells in patients with CRPC were androgen-independent.
Castration-resistant has replaced this term as improved understanding of the mechanisms underlying the development of CRPC have made it clear that, in fact, the AR and AR-driven signaling are frequently still active in these cells.