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= Androgen independent = Androgen independent describes the ability of tumor cells to grow in the absence of androgens. Many early prostate cancers require androgens for growth, but advanced prostate cancers are often androgen-independent.

Androgen receptor
Prostate cancer is dependent on androgen stimulation mediated by the androgen receptor (AR), which belongs to the steroid-receptor superfamily of ligand-dependent transcription factors. Androgens are required for the development of both the normal prostate and prostate cancer. Most patients respond to standard androgen ablation therapies, but virtually all patients eventually relapse with disease that has been termed hormone-refractory or androgen-independent disease. The rate of response to androgen ablation can be as high as 80 percent, but the duration of response is only 12 to 18 months. Efforts to use AR antagonists, such as flutamide or bicalutamide, to enhance responses to primary androgen ablation therapy or to treat androgen-independent prostate cancer have been disappointing, which has diminished enthusiasm for more aggressive or alternative methods to block AR function. However, many lines of evidence indicate that AR function contributes to tumor cell survival after androgen ablation and to growth of androgen-independent prostate cancer.

Mechanisms of androgen independence
Androgens are primary regulators of normal prostate as well as prostate cancer cell growth and proliferation. During androgen-dependent progression, prostate cancer cells depend on the androgen receptor as the primary mediator of growth and survival. During androgen-independent progression, prostate cancer cells develop a variety of cellular pathways to survive and flourish in an androgen-depleted environment. Postulated and documented mechanisms include androgen receptor (AR) gene amplification, AR gene mutations, involvement of coregulators, ligand-independent activation of the androgen receptor, and the involvement of tumor stem cells.

Amplification
Prostate cancer cells develop the ability to use low levels of androgen for survival by increased production of the androgen receptor, increased sensitivity of the androgen receptor to androgen, and by increased local conversion of testosterone to dihydrotestosterone by 5α-reductase (5αR).

Promiscuous binding
Mutations of the androgen receptor broaden binding specificity allowing nonandrogenic steroid molecules normally present in the circulation as well as antiandrogens to bind and activate the androgen receptor.

Outlaw pathway
Non-steroid molecules activate the androgen receptor by ligand-dependent binding or activate downstream signaling of the androgen receptor by ligand-independent mechanisms.

Bypass pathway
Prostate cancer cells develop the ability of survive independent of the androgen receptor. The best known bypass pathway is through modulation of apoptosis by up-regulation of the molecule Bcl-2 by androgen-independent prostate cancer cells which protect them from apoptosis or programmed cell death when they are exposed to lack of testosterone.

Coregulators
Alterations in the balance between coactivators and corepressors, which function as signaling intermediates between the androgen receptor and the transcriptional machinery, influence androgen receptor activation contributing to ability to respond to lower levels of androgen and alternative mechanisms of activation.

Stem cell regeneration
Prostate cancer stem cells, which are not dependent on the androgen receptor for survival, continually resupply the tumor cell population despite therapy.