Androgen independence

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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

The androgen receptor (AR), a member of the steroid-receptor superfamily of ligand-dependent transcription factors, mediates androgen stimulation, which is necessary for the development of prostate cancer . Both the normal prostate and prostate cancer should have androgens to develop . The majority of patients respond to normal androgen deprivation therapy, but almost all of them eventually experience a relapse of the disease known as hormone-refractory or androgen-independent disease. Even though the duration of the response to androgen deprivation is approximately 12 to 18 months, the response rate can reach 80%. It has been considered unsuccessful to utilize AR antagonists, such as flutamide or bicalutamide, to improve responses to primary androgen deprivation therapy or to treat androgen-independent prostate cancer, which has lowered interest in more aggressive or unconventional ways to block AR function. The survival of tumor cells following androgen ablation and the development of androgen-independent prostate cancer are both reportedly influenced by AR activity based on many lines of evidence

Mechanisms of androgen independence

Prostate cancer cell development and proliferation, as well as normal prostate function, are predominantly controlled by androgens. The androgen receptor serves as the main growth and survival mediator in prostate cancer cells during androgen-dependent progression . Prostate cancer cells create a multitude of cellular pathways during androgen-independent development in order to thrive and live in an androgen-depleted environment. There are several hypothesized and proven mechanisms, namely 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

Greater androgen receptor synthesis, increased androgen receptor responsiveness to androgen, and increased local conversion of testosterone to dihydrotestosterone by 5α-reductase (5αR) all contribute to prostate cancer cells' ability to utilize low levels of androgen for survival.

Promiscuous binding

The binding specificity is widened by mutations of the androgen receptor, allowing both antiandrogens and nonandrogenic steroid molecules that are typically present in circulation to bind to 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

The ability to respond to lower levels of androgen and alternate ways of activation are influenced by changes in the balance between coactivators and corepressors, which serve as signaling intermediaries between the androgen receptor and the transcriptional machinery.

Stem cell regeneration

Despite treatment, prostate cancer stem cells, which do not require the androgen receptor for existence, continuously replenish the tumor cell population.

Bibliography

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