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Androgen Receptor Regulation of Prostate Cancer Progression and Metastasis

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Signaling Pathways and Molecular Mediators in Metastasis

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Abstract

Prostate cancer (PCa) is the most commonly diagnosed non-cutaneous malignancy and the second most lethal cancer in men amongst the United States. Localized tumors are effectively treated via radical prostatectomy and/or radiation therapy, however disseminated disease contributes greatly to patient morbidity. At present, therapeutic intervention for metastatic disease capitalizes on the addiction of these tumors to the androgen receptor (AR). The AR signaling axis regulates cell growth, proliferation, and migration of cancer cells, which makes understanding the contribution of AR toward these signaling pathways integral for PCa eradication. Several key signaling molecules are currently known to be controlled by AR and promote migration and invasion in castrate-resistant PCa (CRPC). This concept will be explored with regard to the interplay between AR and chemokine receptors, chromosomal fusions, oncogenes, and microRNAs. Additionally, current and preclinical AR-directed therapeutics used for treatment of metastatic PCa, which impinge on these pathways, and overall AR activity, will be discussed.

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Abbreviations

Abiraterone:

Abiraterone acetate

ADT:

Androgen deprivation therapy

AR:

Androgen receptor

BC:

Bicalutamide (Casodex)

CDKS:

Cyclin-dependent kinases

CML:

Chronic myelogenous leukemia

CRPC:

Castration resistant prostate cancer

CTCs:

Circulating tumor cells

DHT:

5α-dihydrotestosterone

E-Box:

Enhancer box

ETS:

Erythroblast transformation specific transcription factor

FAK:

Focal adhesion kinase

FISH:

Florescence in-situ hybridization

Flutamide:

Hydroxyflutamide

GnRH:

Gonadotropin releasing hormone

HATs:

Histone acetyltransferases

HSPs:

Heat shock proteins

IHC:

Immunohistochemistry

KLF5:

Kruppel-like-factor 5

LBD:

Ligand binding domain

MMPs:

Matrix metalloproteinases

miRNA:

MicroRNA

MYC:

c-Myc

NCoR1:

Nuclear Co-Repressor 1

PIN:

Prostatic intraepithelial neoplasia

PcG:

Polycomb-group

PCa:

Prostate cancer

PSA:

Prostate specific antigen

SDF-1:

Stromal cell-derived factor 1

SFK:

Macrophage inflammatory protein

SRC:

Steroid receptor coactivator

TRAMP:

Transgenic adenocarcinoma of the mouse prostate

TMPRSS2:

Transmembrane protease serine 2

VCaP:

Vertebral-Cancer of the Prostate

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Acknowledgements

We would like to thank all the members of the K. Knudsen lab, especially M. Schiewer, for insightful feedback and critical reading of this chapter.

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Authors and Affiliations

  1. Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA

    R. S. Schrecengost, M. A. Augello & Karen E. Knudsen

  2. Kimmel Cancer Center, Thomas Jefferson University, 233 10th St., BLSB 1008, Philadelphia, PA, 19107, USA

    R. S. Schrecengost, M. A. Augello & Karen E. Knudsen

  3. Department of Urology, Thomas Jefferson University, Philadelphia, PA, USA

    Karen E. Knudsen

  4. Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, USA

    Karen E. Knudsen

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  1. R. S. Schrecengost
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  2. M. A. Augello
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  3. Karen E. Knudsen
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Correspondence to Karen E. Knudsen .

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  1. Drexel University College of Medicine, N. 15th Street 245, Philadelphia, 19102, Pennsylvania, USA

    Alessandro Fatatis

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Schrecengost, R.S., Augello, M.A., Knudsen, K.E. (2011). Androgen Receptor Regulation of Prostate Cancer Progression and Metastasis. In: Fatatis, A. (eds) Signaling Pathways and Molecular Mediators in Metastasis. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-2558-4_12

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