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The development of androgen-independent prostate cancer

Abstract

The normal prostate and early-stage prostate cancers depend on androgens for growth and survival, and androgen ablation therapy causes them to regress. Cancers that are not cured by surgery eventually become androgen independent, rendering anti-androgen therapy ineffective. But how does androgen independence arise? We predict that understanding the pathways that lead to the development of androgen-independent prostate cancer will pave the way to effective therapies for these, at present, untreatable cancers.

Key Points

  • Androgen-independent prostate cancer (AIPC) is an untreatable form of prostate cancer in which the normal dependence on androgens for growth and survival has been bypassed. AIPC is selected for by androgen ablation therapy.

  • The potential mechanisms by which AIPC develops can be divided into five categories.

  • In the hypersensitive pathway, sensitivity to low circulating levels of androgen is increased by amplification of the androgen receptor (AR), mutations in the AR, increased levels of co-activators, or increased production of the potent androgen dihydrotestosterone. Tumours that use this mechanism continue to depend on both androgen and the AR.

  • By contrast, the promiscuous pathway bypasses the need for androgen (but not for AR) by broadening the specificity of the AR so that other steroid hormones — and even AR antagonists — can activate it.

  • Outlaw receptor pathways also bypass the need for androgen. In prostate cancer, outlaw receptors can be produced by crosstalk with growth factor signalling pathways, which lead to phosphorylation and activation of the AR in the absence of androgen.

  • Unlike the three pathways above, the bypass pathway is independent of AR. In this pathway, the pro-apoptotic mechanisms that are normally blocked by androgen are, instead, inhibited by a parallel mechanism such as upregulation of BCL2.

  • In the lurker cell pathway, it is proposed that malignant androgen- and AR-independent epithelial stem cells 'lurking' in the normal prostate become selected for by therapy.

  • By understanding which of these pathways is responsible for AIPC in individual patients, it might be possible to tailor therapies to each patient's needs, thereby outwitting the mechanisms that, so far, have made this disease intractable.

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Figure 1: Androgen action.
Figure 2: Five possible pathways to androgen independence.
Figure 3: The promiscuous androgen receptor.
Figure 4: How growth factor signal transduction creates outlaw receptors.

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Acknowledgements

We thank P. Malloy, A. Krishnan, D. Peehl and R. Roth for helpful discussions.

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Correspondence to David Feldman.

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DATABASE LINKS

CancerNet:

prostate cancer

breast tumours

ovarian tumours

LocusLink:

albumin

sex-hormone-binding globulin

5α-reductase

androgen receptor

protein kinase A

glutathione S-transferase π

SRC1

AIB1

ARA70

TIF2

insulin-like growth-factor-1

keratinocyte growth factor

epidermal growth factor

HER-2/neu

MAPK

PTEN

AKT

BAD

procaspase-9

p27

PI3K

BCL2

 Medscape DrugInfo:

flutamide

casodex

tamoxifen

Herceptin

paclitaxel

FURTHER INFORMATION

Androgen Receptor Gene Mutations Database

Glossary

ACTIVATING DOMAIN

Region of steroid hormone receptors that enhances target gene transcription.

ZINC FINGER

Protein module in which conserved cysteine or histidine residues coordinate a zinc atom. Some zinc-finger regions bind specific DNA sequences; others are involved in protein–protein interactions.

HEAT-SHOCK PROTEINS

(HSP). Molecular chaperones that are induced during cellular stress. They help regulate cellular homeostasis and promote survival.

ANDROGEN RESPONSE ELEMENT

(ARE). Site composed of hexanucleotide repeats and a spacer, usually in the promoter regions of target genes, that contains the androgen receptor zinc-finger-binding region.

GENERAL TRANSCRIPTION APPARATUS

(GTA). A complex of proteins with the potential to facilitate transcription of genes. In vivo specificity of gene transcription by the GTA is regulated by interacting transcription factors.

LNCaP CELLS

A widely studied metastatic prostate cancer cell line that is androgen responsive.

PROSTATE-SPECIFIC ANTIGEN

(PSA). A serine protease in the kallikrein gene family that is secreted into seminal fluid by prostatic epithelial cells and found in the serum. As it is almost exclusively a product of prostate cells, measurement in blood has proved to be exceptionally useful as a tumour marker for diagnosis of prostate cancer and monitoring the effectiveness of treatment.

p160 CO-ACTIVATORS

p160 co-activators are a family of 160-kDa proteins that act as co-activators of nuclear receptors. SRC1 and TIF2 are members of this family.

DOMINANT NEGATIVE

A protein with an inhibitory signal that overrides or blocks a positive signal for transcription.

XENOGRAFT

A graft of tissue or cells transplanted between animals of different species.

PROSTATIC INTRAEPITHELIAL NEOPLASIA

(PIN). Dysplastic cellular changes confined to the prostatic epithelium and considered to be a precursor to adenocarcinoma of the prostate.

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Feldman, B., Feldman, D. The development of androgen-independent prostate cancer. Nat Rev Cancer 1, 34–45 (2001). https://doi.org/10.1038/35094009

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