Sex Steroid Hormones and Genetic Susceptibility to Breast and Prostate Cancer

DRUG METABOLISM REVIEWS, 30(2), 421-434 (1998)

SEX STEROID HORMONES AND G EN ETI C S USC E PTI B I LlTY TO BREAST AND PROSTATE CANCER HEATHER SPENCER FEIGELSON,' RONALD K. ROSS,' MIMI C. YU,' GERHARD A. COETZEE,2 JUERGEN K. V. REICHARDT,3 and BRIAN E. HENDERSON'#* 'Department of Preventive Medicine 2Department of Urology U. S. C. /Norris Comprehensive Cancer Center 1441 Eastlake Avenue Los Angeles, California 90033-0800 9epartment of Biochemistry and Molecular Biology Institute for Genetic Medicine University of Southern California School of Medicine 201 1 Zonal Avenue Los Angeles, California 90033

I. INTRODUCTION ........................................................ 422

11. BREAST CANCER MODEL .......................................... 423 The Cytochrome P450c17a Gene (CYP17) .................... 424

The Estrogen Receptor Gene (ER) ............................... 426

A. B. The 17P-Hydroxysteroid Dehydrogenase 1 Gene

(HSD17Bl) ........................................................... 426 C.

*To whom correspondence should be addressed.

42 1

Copyright 0 1998 by Marcel Dekker, Inc.

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422 FEIGELSON ET AL.

111. PROSTATE CANCER MODEL ...................................... 426 A. The Steroid Sa-Reductase Type I1 Gene (SRD5A2) ......... 427 B. The Androgen Receptor Gene (AR) ............................. 428 C. The Cytochrome P45Oc17a Gene (CYP17) .................... 430

IV. CONCLUSION ........................................................... 430

Acknowledgments ......................................................... 430

References. ................................................................. 430

I. INTRODUCTION

Second only to lung cancer, prostate and breast cancers are the leading causes of cancer death for men and women in the United States, respectively [I]. Whereas some cancers, such as lung and stomach cancers, have shown a decline in incidence from changing environmental exposures, hormone- related cancers, such as breast and prostate cancers, are becoming more prevalent. The development of this latter group of cancers appears to be closely related to endogenous exposure to circulating steroid hormones: estrogen, and perhaps progesterone, in the case of breast cancer, and testosterone and its metabolites in the case of prostate cancer [2]. Although primary and secondary prevention trials using antihormonal agents are un- derway for both of these cancers, their long-term control requires a clearer understanding of the biosynthesis and metabolism of the relevant hormones in vivo [3].

Using the paradigms that have been developed from studies of bladder cancer [4] and using our existing knowledge about the hormone-dependent nature of breast and prostate cancer, we have proposed models for individual susceptibility to these two cancers. In developing these models, we have assumed that within and between ethnic groups there exist genetic differences that affect steroid hormone biosynthesis. Markers (i.e., genetic polymorphisms) of these differences are likely to provide a more precise measure of risk than circulating levels of steroid hormones. The latter measurements are subject to variation by many factors, including time of day of specimen collection, age, menopausal status, disease status, and laboratory impreci- sion. Furthermore, the intracellular concentrations of the active hormones are not necessarily always affected by serum steroid levels. The multigenic models that we have developed for the hormone-related cancers assume that there are functionally important polymorphisms in genes that encode enzymes involved in steroid hormone biosynthesis and metabolism that lead to differ-

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GENETIC SUSCEPTIBILITY TO CANCER 423

ences in individual susceptibility to breast and prostate cancers. We have selected candidate genes based on two criteria: (1) the gene has known polymorphisms that may be functionally relevant and (2) the product of the gene acts in a pathway that is physiologically relevant based on our understanding the etiology of the cancer in question.

There is an important distinction between the genes proposed in these models and susceptibility genes such as BRCAl and BRCA2. Genes like BRCAl and BRCA2 that are necessary and sufficient to cause cancer are very rare and have low population attributable risks. Polymorphisms in “metabolic” genes, such as those described in the following models, are relatively common. So, whereas the at-risk genotypes may each cany a small risk relative to those associated with BRCAl and BRCA2, they likely con- vey much larger population-attributable risks.

In the following sections, we describe our proposed models of breast and prostate carcinogenesis. We also show recent data that are supportive of these models.

11. BREAST CANCER MODEL

Attempts to understand and quantify the role of estrogens in breast cancer have been limited to some extent by our inability to accurately and re- producibly measure steroid hormones in circulating blood. Despite the dif- ficulty of conducting such studies, there is evidence from our group [5-71 and others [8] of significant elevations in circulating estradiol in breast cancer patients compared to controls in populations at both high or low risk of breast cancer. In addition, there are reproducible differences in plasma and urine estrogen levels between healthy high-risk U.S. and low-risk Asian women [6.7]. In one such study in which cycle length was controlled, estradiol levels were 20% higher in Los Angeles compared to Shanghai premenopausal women [6]; in a companion study of postmenopausal women, estradiol levels were 36% higher in Los Angeles than in their matched Japanese counter- parts [7]. Reasons for these differences remain poorly understood, but part of the explanation may be that there are genetic differences that affect metabolism or intracellular binding and transport of estradiol.

Based on the schematic presentation of estrogen metabolism in the ovaries and breast epithelium shown in Fig. l , we describe (below) the function of each of three candidate genes and their possible roles in breast cancer etiology. The genes of interest are the cytochrome P450c17a gene (CYP17), the 17P-hydroxysteroid dehydrogenase 1 gene (HSD17Bl). and the estrogen receptor gene (ER).

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Choleaerol

1 plS(kl'l(CYPI7) Andmetandone

E s m r (El)

17HSD1 (HBDI7Bl)

Estradiol (E2)

17HSDl

E2

FIG. 1. Schematic presentation of 17P-hydroxysteroid dehydrogenase 1 (HSD17B1), cytochrome P450c17a (CYP17), and estrogen receptor (ER) genes in estrogen metabolism in the ovaries and breast epithelium.

A. The Cytochrome P450c17a Gene (CYP17)

CYP17 codes for the cytochrome P450c17a enzyme that mediates both steroid 17a-hydroxylase and 17-20-lyase -activities and functions at key branch points in human steroidogenesis [9]. 17a-Hydroxylase activity con- verts steroids to precursors of the glucocorticoid cortisol, and 17-20-lyase activity yields precursors to estradiol and testosterone.

The 5' untranslated region of CYP17 contains a single base-pair (bp) polymorphism that creates an Spl-type (CCACC box) promoter site 34 bp upstream from the initiation of translation, but downstream from the transcription start site [lo]. This base-pair change also creates a recognition site for the MspAI restriction enzyme. MspAI digestion of a PCR fragment has been used to arbitrarily designate two alleles, A1 (the published sequence) and A2 [lo]. Because this base-pair change creates a CCACC box and it is thought that the number of 5' promoter elements correlates with promoter activity [ 1 I], the A2 allele may result in an increased rate of transcription.

We have reported preliminary findings from a case-control study of breast cancer and this CYP17 polymorphism in which we found an increased risk of advanced breast cancer associated with the A2 allele [odds ratio (OR) = 2.5; 95% confidence interval (CI) = 1.07-5.941 1121. Further, we showed that the A2 allele is associated with an earlier age at menarche among control subjects and that there was an interaction effect between CYP17 genotype and age at menarche on the risk of breast cancer. As shown in Table 1, the protective effect of later age at menarche for breast cancer was more pronounced in women with the Al/Al genotype.

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TABLE

1

Odd

s R

atio

s an

d 95

% C

onfid

ence

Intervals fo

r th

e Risk o

f B

reas

t C

ance

r A

ccor

ding

to

Age

at

Men

arch

e fo

r AU

Subjects a

nd S

ubgr

oups

Str

atifi

ed b

y C

YP1

7 Genotype

AlI

Al

AlI

A2

+ M

IA2

A

ll s

ubje

cts

geno

type

ge

noty

pe

Men

arch

e O

R"

95%

CI

OR"

95%

CI

OR"

95

% C

I

<13

yr

1 .o

-

1 .o

-

1 .o

-

2 13

yr

0.69

0.

47-1

.02

0.47

0.

22-0

.98

0.80

0.

5 1-

1.27

"Adj

uste

d fo

r ag

e, e

thni

city

, and

age

at

first

full-

term

pre

gnan

cy.

Sour

ce:

Ada

pted

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ef.

12.

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These results need to be confirmed in a larger study, and further laboratory investigation is required to determine whether the A 1 /A2 polymorphic site in CYP17 is, in fact, the causative mutation or is simply a marker for another mutation that affects enzymatic activity.

B. The 17B-Hydroxysteroid Dehydrogenase 1 Gene (HSD17Bl)

The HSD17B1 gene codes for the enzyme 17fLhydroxysteroid dehydrogenase type 1 (17HSD1) which catalyzes the final step of estradiol biosynthesis, namely the interconversion of estrone (El) into the more biologically active estrogen, estradiol (E2). 17HSDl acts in the theca cells of the ovary and is expressed in both normal and malignant breast epithelium [ 131.

Several polymorphisms have been identified in the HSD 17B 1 gene [14,15]. Normand et al. [14] described 11 polymorphisms, 2 of which are located in the coding region and result in amino acid changes. Neither polymorphism appears to substantially affect the catalytic or the immunological properties of the enzyme [16], but one (a serine to glycine change at position 312) has been shown to be associated with a marginally statistically significant increased risk for breast cancer [ 151. We are currently evaluating this polymorphism in a case-control study of breast cancer.

C. The Estrogen Receptor Gene (ER)

Several polymorphisms in the ER gene have been reported [17-201. The most promising evidence for an association between ER gene polymorphisms and breast cancer risk was reported by Andersen et al. [19], who examined three Restriction Fragment-Length Polymorphisms (RFLPs) and found that alleles having an XbaI restriction site were significantly more frequent in breast cancer patients than controls (OR = 2.0). This association was limited to postmenopausal patients. Del Senno et al. [20] reported a highly polymorphic (TA), repeat upstream from the region of the ER gene originally described as exon 1 in the transactivation domain. This is a potentially in- teresting region, as the ER has recently been shown to have at least three different promoters that exhibit tissue-specific expression [2 1-24]. Further characterization of this region could provide important clues for understanding the role of the ER gene in breast cancer. We have initiated studies of the XbaI polymorphism and the (TA), repeat in breast cancer.

111. PROSTATE CANCER MODEL

Increased cell division is the hallmark of the response of prostate epithelial cells to androgens. Specifically, cell division in the prostate is controlled by

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4 4 P45Oc17 (CWI7)

Pregnenolone

Androstenedine

Testosterone (T) 4

Testicular Biosynthesis Rostate Qithelial Cell I Cholesterol 1 I

/ (k) _.) DNA

Dihydrotestosterone @HT)

1 sRD5A2

- -b Testosterone(T) - FIG. 2. Schematic presentation of steroid Sa-reductase (SRDSA2),

cytochrome P450c17a (CYP17). and androgen receptor (AR) activity in testosterone metabolism in the testicles and prostate epithelium.

testosterone (T), following its intracellular conversion to dihydrotestosterone (DHT), as shown in Fig. 2. This conversion is catalyzed by the enzyme steroid Sa-reductase type 11. DHT and, much less efficiently, T bind to the androgen receptor (AR) in the cytoplasm, and the ARAigand complexes are translocated to the nucleus for DNA binding and transactivation of target genes, including those that control cell division and death.

Ethnicity is an important determinant of prostate cancer risk. African- Americans have higher rates than whites who, in turn, have higher rates than U.S.-born Asians [25]. Differences among ethnic groups with respect to serum testosterone levels [26] and steroid Sa-reductase activities as measured by the DHT metabolite, Sa-androstane-3a, 17P-diol- 17P-glucuronide (AAG) have been suggested to explain, at least in part, the large ethnic variability in the incidence of prostate cancer [27]. The genes of interest to us currently are the steroid Sa-reductase gene type I1 (SRDSA2), the androgen receptor gene (AR), and the cytochrome P450c17a gene (CYP17).

A. The Steroid 5a-Reductase Type I1 Gene (SRD5A2)

There are two distinct steroid Sa-reductase enzymes encoded for by different genes; the type I1 enzyme is active primarily in the prostate and in genital skin. Germline mutations of the type I1 gene (SRDSA2) have been identified, most notably in a sizable kindred in the Dominican Republic [28]. Boys with this mutated gene are phenotypically female with a persistent vaginal pouch until puberty, at which time there is some phallic enlargement and development of some secondary sex characteristics, but the prostate remains underdeveloped.

Davis and Russell [29] have described a polymorphism (TA repeat number) in the 3' untranslated region of the SRDSA2 gene. We have confirmed

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this polymorphism [30], but find the prevalence of variant alleles using this polymorphic marker to be substantially higher than that reported by Davis and Russell.

We have also identified additional polymorphisms in the gene [31], including a functional substitution in exon 1 that changes the amino acid at position 89 from valine to leucine (V89L). As shown in Table 2, the leucine (L) allele is more common in Asians and is associated with lower levels of circulating AAG (a metabolite of DHT). These data may provide an explanation for the low risk of prostate cancer in Asian populations.

B. The Androgen Receptor Gene (AR)

It is likely that the AR also is involved in the racial-ethnic variation in prostate cancer incidence. The AR gene, on the long arm of the X chromo- some, belongs to the superfamily of ligand-dependent transactivation factors and, like others in this family, contains a C-terminal hormone-binding domain, a central DNA-binding domain, and an N-terminal transcriptional modulatory domain which, for the AR gene, is encoded entirely by exon 1 [32].

Within exon 1 , there are two highly polymorphic microsatellites; one of these is a trinucleotide (CAG) repeat sequence of unknown function. Abnor- mal expansion of this satellite is causally associated with X-linked spinal and bulbar muscular atrophy (Kennedy’s disease) [33]. The normal size varies from 9 to 31 repeats, whereas the mutant range associated with Kennedy’s disease varies from 40 to 62. It was demonstrated that these mutant recep- tors have normal androgen binding, but in transfection assays, they trans- activate an androgen responsive reporter gene subnormally [34]. We and others have noted that African-Americans, U. S. whites, and Asian-Ameri- cans show population differences in the CAG repeat polymorphism of the AR locus, with the allele frequency distribution shifted toward shorter alleles in the case of African-Americans and longer alleles in the case of Asians relative to whites [35,36]. We have hypothesized that this size polymorphism might correlate with, or cause changes in, AR function (smaller size, greater transactivity) and, therefore, possibly also be associated with prostate cancer risk [36]. We and others have demonstrated this association in case- control comparisons in Caucasian populations [37-391. However, it is unclear whether this polymorphism is the functionally relevant change as described above, or a marker for another nearby functional polymorphism.

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C. The Cytochrome P450c17a Gene (CYP17)

As described in the breast cancer model, the cytochrome P450c17a enzyme yields precursors to estradiol and testosterone. We are evaluating the CYP17 polymorphism to determine if it also plays a role in prostate cancer.

IV. CONCLUSION

Both breast and prostate cancers exhibit substantial unexplained differences in risk across ethnic groups. The role of metabolic genes in carcinogenesis and in explaining racial-ethnic variation in risk is a relatively new area of research with scant information at present. Investigating functionally relevant polymorphisms in these genes should help us understand the underlying etiology of these two cancers and lead to more refined definitions of “high-risk” individuals. Ultimately, this should enable us to better define who may benefit from specific interventions based on underlying genetic susceptibility and provide important targets for prevention and control.

ACKNOWLEDGMENTS

This work was support by grants R01 CA54281, CA63464, CA68581, and R35 CA53890 from the National Cancer Institute and by grant 2FB-0212 from the University of California Breast Cancer Research Program.

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