A Review of the Expression of Genes Involved in Sex Steroid Hormone Metabolism and Activity in Prostate Tissue: A Need for Epigenetic Information

Jamie Ritchey1, MPH; Wilfried Karmaus1, MD, Dr.med, MPH; Tara Sabo-Attwood1,2, PhD; Susan E. Steck1,3, PhD, MPH, RD; Hongmei Zhang1, PhD; 1Department of Epidemiology and Biostatistics, 2Department of Environmental Health Sciences, 3Cancer Prevention and Control Program, University of SouthCarolina, 800 Sumter Street, Columbia, SC 29208.

INTRODUCTION

• A pathway-oriented approach guided the literature searches, conducted in Pub Med, limited to English language and human prostate only

OBJECTIVE• To review the literature for gene expression of enzymes and receptors involved in sex steroid hormone metabolism and activity in normal, benign, and cancerous prostate tissues

• To determine if there is an association with gene expression and age, body mass index, estrogen and testosterone levels, and cancer treatments

METHODS

RESULTS

REFERENCES

RATIONALE

• Age, race, and family history are the only confirmed risk factors for prostate cancer [1]

• Observational, clinical, and laboratory evidence indicate that sex steroid hormones are important to the development and progression of prostate cancer [2-14]

• Epidemiology focusing on sex steroid hormone risk and prostate cancer is inconclusive [2-14]

• Most epidemiologic studies have focused on gene single nucleotide polymorphisms (SNPs) of hormone metabolic enzymes and serum hormone levels [2-3]

• Gene expression may provide etiologic clues regarding how sex steroid metabolism is associated with prostate cancer not detected at the DNA sequence or serum level [130]

• The expression of genes involved in sex steroid metabolism in prostate tissues may differ by different levels of age, body mass index, race, estrogen and testosterone levels, and/or cancer treatments administered

STRENGTHS

LIMITATIONS

• To guide our searches, we constructed a figure of a

plausible gene network for E and T expression [3,11, 19-20].

• Past studies have only included portions of pathways, or the T or E pathways alone, and often do not include preliminary pathways (the dashed line from androstenedione to DHT indicates that this reaction is preliminary) [3,11,19-20].

• Used a pathway approach to guide searches

• Omitted cell studies since results may not be consistent with tissue studies for methodological reasons

• Reviewed references cited in publications found during searches to improve completeness

• Information for many genes was scant

• Only publications in English language were considered

• Only includes citations from PubMed

SUMMARY• GSTP1 was consistently down regulated or not expressed in prostate cancer, which coincides with previous research indicating that GSTP1 is methylated in prostate cancer tissue [16,95,99-109,111-118,130,136]

• For all other genes, studies were either scant or inconsistent, and conflicting expression results may be due to limitations, including: tissue collection, laboratory methods, or gene functionality

• Few studies were found examining the association of gene expression with age, race, body mass index, estrogen, testosterone, and cancer treatments

• Future studies should focus not only on gene expression, but also epigenetic mechanisms such as methylation to assess prostate cancer risk

Table 1. Literature search summary

Gene &

Chromosomal location

Total articles

retrieved

Laboratory

methods†

Androgen Metabolism

AR

Ch Xq12

26 IHC, Microarrays, IS, ISV, real-time PCR

HSD17B2

Ch 16q24.1-q24.2

4 IHC, ISH, Microarray, real-time PCR

HSD17B3

Ch 9q22

4 IHC, microarray, real-time PCR

SRD5A1

Ch 5p15.31

6 IHC, ISH, Microarray

SRD5A2

Ch 2p23.1

10 IHC, ISH, Microarray, real-time PCR

CYP3A4

Ch 7q21.1-22

5 IHC, real-time PCR

CYP3A5

Ch 7q21.1-22

6 IHC, real-time PCR, meta-analysis

CYP3A7

Ch 7q21.1-22

3 IHC, real-time PCR

CYP3A43

Ch 7q21.1

1 ICH, real-time PCR

AKR1C3

Ch 10p15-14

6 Array, real-time PCR, Northern blot, review

AKR1C2

Ch 10p15-14

5 Array, real-time PCR, review

HSD3B1

Ch 1p13-11

2 Array, real-time PCR

HSD3B2

Ch 1p13.1

3 Array, review

UGT2B15

Ch 4q13

3 Array, microarray

UGT2B17

Ch 4q13

3 IHC, ISH, real-time PCR

Estrogen Metabolism

ESR1

Ch 6q24-27

9 IHC, ISH, real-time PCR

ESR2

Ch 14q31-22

10 IHC, ISH, microarray, real-time PCR

CYP19A1

Ch 15q21

9 Avidin-biotin, IHC, ISH, microarray, real-time PCR

HSD17B1

Ch 17q11-21

2 IHC, real-time PCR

HSD17B4

Ch 5q2

5 IHC, ISH, microarray, real-time PCR, meta-analysis

HSD17B7

Ch 1q23

1 IHC

SULT1A1

Ch 16p21.1

3 IHC, Western blot

SULT1A3

Ch 16p11.2

2 IHC, Western blot

SULT2B1a

Ch 19 q13.3

3 Northern blot, immunoblot, IHC

SULT2Bb

Ch 19 q13.3

3 Northern blot, immunoblot, IHC

HSD17B12

Ch 11p11

1 IHC, ISH

CYP1A1

Ch 15q24.1

4 IHC, real-time PCR

CYP1A2

Ch 15q24.1

4 IHC, real-time PCR

CYP1B1

Ch 2p22.2

6 IHC, ISH, real-time PCR

COMT

Ch 22q11.21

2 IHC, real-time PCR

GSTT1

Ch 22q11.23

1 Microarray, real-time PCR

GSTM1

Ch 1p13.1

3 IHC, microarray, real-time PCR

GSTP1

Ch 11q13.2

10 IHC, IS, microarray, real-time PCR

†Laboratory method abbreviations: Immunohistochemistry (IHC), Real-time polymerase chain reaction (real-time PCR), Immunostaining (IS), In situ

hybridization (ISH), Immunostaining with optimized IHC criteria and video image analysis (ISV)

• A total of 85 studies were identified

• Most studies focused on the expression of one or a few genes, rather than the complete pathway, ignoring compensatory or alternate response

• Studies comparing normal, benign, and cancerous prostate tissue showed limited consistency, with one exception, the down-regulation of GSTP1 in cancerous tissue

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Figure 1. A plausible gene expression network for genes and receptors involved in Estrogen (E) and Testosterone (T) metabolism in the prostate [3, 11, 19-20]