[Frontiers in Bioscience 12, 3436-3460, May 1, 2007]
Molecular epidemiology of prostate cancer: hormone-related genetic loci
Anand P. Chokkalingam 1, Frank Z. Stanczyk 2, Juergen K.V. Reichardt 3, Ann W. Hsing 4
1 Division of Epidemiology, School of Public Health, University of California, 2150 Shattuck Ave, Ste 500, Berkeley, CA 94707,
USA, 2 Departments of Obstetrics and Gynecology and Preventive Medicine, University of Southern California, Women's and
Children's Hospital, Room 1M2, 1240 North Mission Road, Los Angeles, CA 90033, USA, 3 Plunkett Chair of Molecular Biology
(Medicine), University of Sydney, Medical Foundation Building (K25)92-94 Parramatta Road, Camperdown, NSW 2006,
Australia, 4 Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Blvd EPS 5024, Bethesda,
MD 20892, USA
TABLE OF CONTENTS
3.1. Biosynthesis and metabolism of androgens
3.2. Androgen action on the prostate
3.3. Androgens and prostate cancer: epidemiologic evidence
3.4. Androgen-related genes
3.4.1. AR and AR coactivators
3.4.5. HSD3B and HSD17B
4. Estrogens and estrogen receptors
4.1. Estrogens in prostate cancer
4.2. Estrogen receptors in prostate cancer
4.3. Estrogen-related genes
5. Sex hormone-binding globulin (SHBG)
5.1. Role of SHBG in sex hormone transport
5.2. Role of SHBG in prostate cancer
6. Insulin and Leptin
6.1. Circulating insulin and leptin levels and prostate cancer
6.2. Insulin and leptin genes
7. Insulin-like growth factor (IGF) axis
7.1. IGF axis and prostate cancer
7.2. IGF axis genes
8. Vitamin D
8.1. Vitamin D and prostate cancer
8.2. Vitamin D receptor (VDR) gene
10. Future Directions
10.1. Studies of hormones in prostate tissue
10.2. Studies of hormones in circulation
10.3. Studies of genes
Prostate cancer is the most common non-skin
cancer and the second leading cause of cancer deaths
among men in most Western countries. Despite its high
morbidity and mortality, the etiology of prostate cancer
remains obscure. Although compelling laboratory data
suggest a role for androgens in prostate carcinogenesis,
most epidemiologic data, including serological and
genetic studies, are inconclusive. In this chapter, we
review the status of serologic studies and discuss
the importance of intra-prostatic hormone levels in possibly
clarifying the often-contradictory data on serologic studies.
To provide insights and directions for epidemiologic
research on hormones and prostate cancer, this review
centers on the molecular epidemiology of hormone-related
genetic loci. These loci have been investigated in a number
of studies to date and will undoubtedly expand even further
as rich new genetic information sources and high-
throughput genotyping and analysis methods become
Hormone-related genes and prostate cancer
available. Due to the enormous number of these loci, we
recommend careful analysis and cautious interpretation of
studies of genetic markers, including microsatellites and
single nucleotide polymorphisms (SNPs), as false positive
and negative results are likely due to limited statistical
power, multiple hypothesis
stratification, or non-representative population sampling.
This review also highlights the need for replication in
various populations, as well as reasons for performing
functional analyses of SNPs, a critical and often under-
appreciated component of molecular epidemiologic
investigations. The time is ripe for concerted, large-scale
multidisciplinary investigations that incorporate molecular
genetics, biochemistry, histopathology, and endocrinology
into traditional epidemiologic studies. Such collaboration
will lead to a deeper understanding of the etiologic
pathways of prostate cancer, ultimately yielding better
preventive, diagnostic, and therapeutic strategies.
Prostate cancer is the most common non-skin
cancer among American men, with 234,460 new cases
expected in 2006, and it ranks third in number of estimated
male cancer deaths (n=27,350), behind only lung and
colorectal cancer (1). Despite the magnitude of prostate
cancer incidence and mortality, few risk factors have been
identified other than age, race, and family history.
Prostate cancer is a hormone-mediated cancer.
Abundant biological data have shown that the growth and
maintenance of the prostate are dependent on androgens,
that prostate cancer regresses after androgen ablation or
anti-androgen therapy, and that administration of
testosterone induces prostate tumors in laboratory animals
(2-4). Estrogen compounds have long been used to control
prostate cancer growth, though recognition of their serious
cardiac and sexual side effects have diminished their use
(5). Similarly, strong laboratory evidence shows that
vitamin D, another steroid hormone, has strong anti-
proliferative and pro-apoptotic effects on prostate cancer
(6). In addition, obesity, which has been linked to elevated
risk of aggressive prostate cancer and prostate cancer death
(7), is associated with lower levels of sex hormone-binding
globulin (SHBG) and presumably higher levels of free
testosterone (8). However, despite numerous studies of
both prospective and retrospective designs, there has been
no convincing epidemiological evidence linking circulating
levels of these hormones to prostate cancer risk (6, 9). A
number of methodological issues, discussed below, have
been suggested to explain these inconsistencies.
Family history is an established risk factor for
prostate cancer: men with a first-degree affected relative
(father, brother) have a 2-3-fold increased risk (10), and it
has been estimated that 42% (95% CI 29-50%) of prostate
cancer risk is explained by genetic factors, the highest for
any human cancer (11). More recent epidemiological
investigations have attempted to exploit this known
heritability by focusing on hormone-related genes as a path
to understanding the role of hormones in prostate cancer.
However, though these studies provide exciting new
evidence and leads regarding the specific roles played by
hormones and hormone-related genetic loci, results to date
have not been conclusive. Indeed, despite the large number
of publications resulting from the sudden wealth of genetic
data enabled by recent genotyping technology advances,
few of the reported findings have been replicated (12), and
this trend is likely to continue as the technologies improve
further. It is possible that the familial and sporadic forms
of the disease are etiologically distinct.
This review summarizes current perspectives on
steroid hormone metabolism, epidemiologic data on
androgenic and non-androgenic hormones in prostate
cancer, and polymorphisms of genes involved in androgen
metabolism and regulation. Through this effort, we attempt
to provide insights and directions for future research on
hormone-related genetic loci and prostate cancer.
3.1. Biosynthesis and Metabolism of Androgens
Androgens are steroid hormones that induce the
differentiation and maturation of the male reproductive
organs and the development of male secondary sex
characteristics. In men, androgens are formed primarily
in the testes and the adrenal gland, and to a lesser extent
in peripheral tissues, such as the prostate and skin.
Formation of androgens in the endocrine glands occurs
by well-characterized biosynthetic pathways (Figure 1).
Testosterone is the principal androgen in
circulation, while dihydrotestosterone (DHT) is the
primary nuclear androgen and the most potent androgen.
In the circulation of adult males, roughly 44% of
testosterone is bound with high affinity to SHBG, 54%
is bound with low affinity to albumin, and only 1-2% of
testosterone exists in a free (unbound) state. About 25%
of the DHT in the circulation is secreted by the testes,
while most (65-75%) arises from conversion of
testosterone in peripheral tissue in a reaction catalyzed
by the enzyme steroid 5 alpha-reductase or from
circulating inactive androgens, such as androstenedione,
dehydroepiandrosterone (DHEA), and DHEA sulfate
(DHEAS). In humans, two steroid 5 alpha-reductase
isoenzymes have been identified. The type 1 enzyme
(encoded by the SRD5A1 gene) is expressed mostly in
skin and hair, whereas the type 2 enzyme (encoded by
the SRD5A2 gene) is localized primarily in androgen
target tissue, including genital skin and the prostate
In men, the prostate is a major site of non-
testicular DHT production from testosterone. Free
testosterone in circulation enters prostate cells by passive
diffusion, whereas albumin-bound testosterone, because of
its low affinity for albumin, can disassociate from albumin,
allowing it to enter prostatic cells. In addition, recent
evidence of SHBG receptors on the surface of prostate cells
suggests that SHBG-bound testosterone may also enter
prostate cells (14, 15). Figure 2 shows the metabolic
pathways of androgens within the prostate gland.
Hormone-related genes and prostate cancer
Figure 1. Androgen metabolism pathways in the endocrine system.
The concentration of DHT in serum is a fraction
of that of testosterone (16), whereas the concentration of
DHT in prostatic tissue is several times higher than that of
testosterone, suggesting that DHT levels in tissue are
important in prostate development and tumorigenesis.
However, tissue levels of testosterone and DHT are
difficult to measure in epidemiologic studies, and thus, the
serum concentration of 3 alpha-diol G (3 alpha
androstanediol glucuronide; AAG) is commonly used as an
indirect measure of steroid 5alpha-reductase enzymatic
activity or, more generally, of intra-prostatic androgenicity.
The concentration of 3alpha-diol G in serum correlates well
with steroid 5alpha-reductase activity in genital skin (17,
18). Although serum levels of 3alpha-diol G may reflect
enzyme activities of both the type 1 and type 2 steroid
5alpha-reductase enzymes, recent data from studies of
finasteride, a type 2 steroid 5alpha-reductase inhibitor,
show that serum levels of DHT and 3alpha-diol G decrease
concomitantly in treated men, suggesting that serum levels
of 3alpha-diol G may predominantly reflect the activity of
the type 2 steroid 5alpha-reductase (19).
3.2 Androgen Action on the Prostate
The action of DHT in the prostate is mediated by
the androgen receptor (AR) (Figure 2). Within the prostate,
DHT binds to the AR to form an intracellular complex
which binds to androgen-response elements in the DNA of
prostate cells, ultimately inducing proliferation. Though
the tissue concentration of DHT necessary to initiate the
androgen cascade is unknown, just a minute amount is
required to trigger androgenic action in prostate cancer
patients who have undergone androgen ablation treatment,
perhaps because such patients have hypersensitive ARs (20,
21). In the absence of androgen, non-androgenic hormones
including estradiol, vitamin D, and insulin-like growth
factors (IGFs) can bind ARs, triggering androgenic action
(22, 23). In addition, the activity of the AR is modulated
by a series of coactivator proteins, including ARA54,
ARA55, ARA70, ARA160, p160, BRCA1, AIB1, and
CBP, which can enhance AR transcriptional activity
several-fold (24-26). Thus, androgenic action within the
prostate is determined not only by androgen concentration
but also by numerous other factors, including factors yet to
be identified. However, no epidemiologic studies have
directly assessed tissue hormone levels or androgenic
action within the prostate, due in part to the difficulty in
collecting prostate tissue from control subjects in case-
control studies, or from men at baseline in cohort studies.
3.3. Androgens and Prostate Cancer: Epidemiologic
Most epidemiologic studies have compared
serum levels of androgens in prostate cancer cases with
those in healthy subjects in either case-control or
prospective studies. In case-control studies, blood samples
from cancer patients are collected after diagnosis (usually
before treatment) and assayed for hormone levels. Thus,
the presence of disease may have an effect on circulating
levels of hormone. Moreover, these types of cross-
sectional studies make it difficult to establish a temporal
relationship between androgens and prostate cancer. In
contrast, prospective studies, such as nested case-control
studies, compare serum levels of hormones in pre-
diagnostic blood samples from incident cases identified in a
prospective follow-up to those of healthy controls selected
from the same cohort. Because blood samples of the case
subjects are usually collected several years before the
diagnosis of cancer, potential effects of disease on the
measurement of hormones are presumably minimized.
Several prospective studies have evaluated the
role of serum hormones in prostate cancer. Although two
Hormone-related genes and prostate cancer
Figure 2. Androgen metabolism pathways within the prostate gland.
studies reported a statistically significant association
between serum levels of testosterone and prostate cancer
(16, 27), several found suggestive, but statistically non-
significant, associations between prostate cancer and serum
levels of testosterone and DHT (28, 29). Recent studies
have shown elevated risk of low-grade prostate cancer and
reduced risk of high-grade prostate cancer to be associated
with higher levels of serum testosterone (30, 31). This
might explain, in part, inconsistent results of studies linking
obesity to both increased risk of aggressive prostate cancer
and decreased risk of overall and low-grade tumors (7), as
obesity is associated with lower serum levels of androgens
(8). Earlier studies using the ratio of serum testosterone to
DHT as an indirect measure of steroid 5alpha-reductase
type 2 activity, suggested a role for the steroid 5alpha-
reductase type 2 enzyme (28, 29). However, more recent
studies have found no significant association between
prostate cancer risk and serum levels of 3alpha-diol G, a
surrogate marker for steroid 5alpha-reductase activity
within the prostate (16, 31-37).
In most of these studies, the failure to show an
association between androgen levels and prostate cancer
risk may be due, in part, to methodologic limitations that
include difficulty in making reliable measurements of
circulating hormone levels in an epidemiologic setting. It
is possible that free, unbound testosterone is more
etiologically relevant than total testosterone, but because it
is infeasible to directly measure free testosterone in
epidemiological studies, its concentration is often estimated
indirectly from measures of total testosterone and SHBG.
Moreover, the statistical power of some studies is often
limited by small sample size, by the observation of
relatively small differences (usually 10-15%) between
cases and controls, or by fairly large intra- and inter-assay
laboratory variations in circulating hormone assays (38). In
addition, it is unclear whether circulating levels of
androgens reflect the androgenic environment within the
prostate, since DHT in the prostate gland mainly comes
from intra-prostatic conversion of testosterone. Also
unclear is whether cumulative exposure to androgens
over a lifetime or exposure at certain points in life is
more relevant in prostate carcinogenesis. Hormonal
changes during the prenatal and peri-pubertal period
may be of etiologic importance, because prostate
development, including substantial epithelial cell
differentiation, occurs at these critical time periods (39).
Accordingly, if early exposure to androgens is most
critical for the development of prostate cancer, then
most epidemiologic studies that measure circulating
hormone levels of hormones in study subjects who are
typically in their sixth decade of life would miss the
etiologically relevant period of exposure. Thus very
long-term studies may be needed to examine this
hypothesis. Lastly, the heterogeneity of prostate cancer
may influence results, as evidenced by the different
findings observed for serum testosterone by tumor
aggressiveness (30). Future studies will need to address
this by stratifying by disease grade and/or stage.
A better understanding of the hormonal milieu
within the prostate gland and its relationship to circulating
hormones would be critical to interpret results from serum-
based studies. However, epidemiologic studies of tissue
androgen levels are impeded by various methodologic
problems associated with prostate tissue collection and
methods for tissue hormone measurements. These
problems are compounded by the lack of a normal
comparison group for analytic studies, since ethical
considerations often preclude the collection of “normal”
tissue from healthy subjects. In addition, the high
prevalence of latent prostate tumors in elderly men means
that identification of age-matched controls with no
histological evidence of prostate cancer is very difficult.
Hormone-related genes and prostate cancer
meta-analysis. Cancer Epidemiol Biomarkers Prev, 12,
116. Margiotti, K., E. Kim, C. L. Pearce, E. Spera, G.
Novelli & J. K. Reichardt: Association of the G289S single
nucleotide polymorphism in the HSD17B3 gene with
prostate cancer in Italian men. Prostate, 53, 65-8. (2002)
117. Chang, B. L., S. L. Zheng, G. A. Hawkins, S. D.
Isaacs, K. E. Wiley, A. Turner, J. D. Carpten, E. R.
Bleecker, P. C. Walsh, J. M. Trent, D. A. Meyers, W. B.
Isaacs & J. Xu: Joint effect of HSD3B1 and HSD3B2 genes
is associated with hereditary and sporadic prostate cancer
susceptibility. Cancer Res, 62, 1784-9. (2002)
118. Kraft, P., P. Pharoah, S. J. Chanock, D. Albanes, L. N.
Kolonel, R. B. Hayes, D. Altshuler, G. Andriole, C. Berg,
H. Boeing, N. P. Burtt, B. Bueno-de-Mesquita, E. E. Calle,
H. Cann, F. Canzian, Y. C. Chen, D. E. Crawford, A. M.
Dunning, H. S. Feigelson, M. L. Freedman, J. M. Gaziano,
E. Giovannucci, C. A. Gonzalez, C. A. Haiman, G.
Hallmans, B. E. Henderson, J. N. Hirschhorn, D. J. Hunter,
R. Kaaks, T. Key, L. L. Marchand, J. Ma, K. Overvad, D.
Palli, M. C. Pike, E. Riboli, C. Rodriguez, W. V. Setiawan,
M. J. Stampfer, D. O. Stram, G. Thomas, M. J. Thun, R.
Travis, A. Trichopoulou, J. Virtamo & S. Wacholder:
Genetic Variation in the HSD17B1 Gene and Risk of
Prostate Cancer. PLoS Genet, 1, e68 (2005)
119. Rebbeck, T. R., J. M. Jaffe, A. H. Walker, A. J. Wein
& S. B. Malkowicz: Modification of clinical presentation of
prostate tumors by a novel genetic variant in CYP3A4. J
Natl Cancer Inst, 90, 1225-9. (1998)
120. Zeigler-Johnson, C. M., A. H. Walker, B. Mancke, E.
Spangler, M. Jalloh, S. McBride, A. Deitz, S. B.
Malkowicz, D. Ofori-Adjei, S. M. Gueye & T. R. Rebbeck:
Ethnic differences in the frequency of prostate cancer
susceptibility alleles at SRD5A2 and CYP3A4. Hum
Hered, 54, 13-21 (2002)
121. Bangsi, D., J. Zhou, Y. Sun, N. P. Patel, L. L. Darga,
L. K. Heilbrun, I. J. Powell, R. K. Severson & R. B.
Everson: Impact of a genetic variant in CYP3A4 on risk
and clinical presentation of prostate cancer among white
and African-American men. Urol Oncol, 24, 21-7 (2006)
122. Plummer, S. J., D. V. Conti, P. L. Paris, A. P. Curran,
G. Casey & J. S. Witte: CYP3A4 and CYP3A5 genotypes,
haplotypes, and risk of prostate cancer. Cancer Epidemiol
Biomarkers Prev, 12, 928-32 (2003)
123. Zeigler-Johnson, C., T. Friebel, A. H. Walker, Y.
Wang, E. Spangler, S. Panossian, M. Patacsil, R. Aplenc,
A. J. Wein, S. B. Malkowicz & T. R. Rebbeck: CYP3A4,
CYP3A5, and CYP3A43 genotypes and haplotypes in the
etiology and severity of prostate cancer. Cancer Res, 64,
124. Zhenhua, L., N. Tsuchiya, S. Narita, T. Inoue, Y.
Horikawa, H. Kakinuma, T. Kato, O. Ogawa & T. Habuchi:
CYP3A5 gene polymorphism and risk of prostate cancer in
a Japanese population. Cancer Lett, 225, 237-43 (2005)
125. Kuehl, P., J. Zhang, Y. Lin, J. Lamba, M. Assem, J.
Schuetz, P. B. Watkins, A. Daly, S. A. Wrighton, S. D.
Hall, P. Maurel, M. Relling, C. Brimer, K. Yasuda, R.
Venkataramanan, S. Strom, K. Thummel, M. S. Boguski &
E. Schuetz: Sequence diversity in CYP3A promoters and
characterization of the genetic basis of polymorphic
CYP3A5 expression. Nat Genet, 27, 383-91 (2001)
126. Farnsworth, W. E.: Estrogen in the etiopathogenesis of
BPH. Prostate, 41, 263-74 (1999)
127. Gupta, C.: The role of estrogen receptor, androgen
receptor and growth factors in diethylstilbestrol-induced
programming of prostate differentiation. Urol Res, 28, 223-
128. Shirai, T., M. Sano, K. Imaida, S. Takahashi, T. Mori
& N. Ito: Duration dependent induction of invasive
prostatic carcinomas with pharmacological dose of
testosterone propionate in rats pretreated with 3,2'-
dimethyl-4-aminobiphenyl and development of androgen-
independent carcinomas after castration. Cancer Lett, 83,
129. Bosland, M. C., H. Ford & L. Horton: Induction at
high incidence of ductal prostate adenocarcinomas in
NBL/Cr and Sprague-Dawley Hsd:SD rats treated with a
combination of testosterone and estradiol-17 beta or
diethylstilbestrol. Carcinogenesis, 16, 1311-7 (1995)
130. Strohsnitter, W. C., K. L. Noller, R. N. Hoover, S. J.
Robboy, J. R. Palmer, L. Titus-Ernstoff, R. H. Kaufman, E.
Adam, A. L. Herbst & E. E. Hatch: Cancer risk in men
exposed in utero to diethylstilbestrol. J Natl Cancer Inst,
93, 545-51 (2001)
131. Lau, K. M., M. LaSpina, J. Long & S. M. Ho:
Expression of estrogen receptor (ER)-alpha and ER-beta in
normal and malignant prostatic epithelial cells: regulation
by methylation and involvement in growth regulation.
Cancer Res, 60, 3175-82 (2000)
132. Gustafsson, J. A.: An update on estrogen receptors.
Semin Perinatol, 24, 66-9 (2000)
133. Srinivasan, G., E. Campbell & N. Bashirelahi:
Androgen, estrogen, and progesterone receptors in normal
and aging prostates. Microsc Res Tech, 30, 293-304 (1995)
134. Weihua, Z., S. Makela, L. C. Andersson, S. Salmi, S.
Saji, J. I. Webster, E. V. Jensen, S. Nilsson, M. Warner &
J. A. Gustafsson: A role for estrogen receptor beta in the
regulation of growth of the ventral prostate. Proc Natl Acad
Sci U S A, 98, 6330-5 (2001)
135. Rosner, W., D. J. Hryb, M. S. Khan, A. M. Nakhla &
N. A. Romas: Sex hormone-binding globulin mediates
steroid hormone signal transduction at the plasma
membrane. J Steroid Biochem Mol Biol, 69, 481-5 (1999)
136. Nakhla, A. M., N. A. Romas & W. Rosner: Estradiol
activates the prostate androgen receptor and prostate-
specific antigen secretion through the intermediacy of sex
hormone-binding globulin. J Biol Chem, 272, 6838-41
137. Farnsworth, W. E.: Roles of estrogen and SHBG in
prostate physiology. Prostate, 28, 17-23 (1996)
138. Fortunati, N., M. Becchis, M. G. Catalano, A. Comba,
P. Ferrera, M. Raineri, L. Berta & R. Frairia: Sex hormone-
binding globulin, its membrane receptor, and breast cancer:
a new approach to the modulation of estradiol action in
neoplastic cells. J Steroid Biochem Mol Biol, 69, 473-9
139. Plymate, S. R., S. M. Loop, R. C. Hoop, K. M. Wiren,
R. Ostenson, D. J. Hryb & W. Rosner: Effects of sex
hormone binding globulin (SHBG) on human prostatic
carcinoma. J Steroid Biochem Mol Biol, 40, 833-9 (1991)
140. Peiris, A. N., J. I. Stagner, S. R. Plymate, R. L. Vogel,
M. Heck & E. Samols: Relationship of insulin secretory
Hormone-related genes and prostate cancer
pulses to sex hormone-binding globulin in normal men. J
Clin Endocrinol Metab, 76, 279-82 (1993)
141. Hsing, A. W., J. Deng, I. A. Sesterhenn, F. K. Mostofi,
F. Z. Stanczyk, J. Benichou, T. Xie & Y. T. Gao: Body size
and prostate cancer: a population-based case-control study
in China. Cancer Epidemiol Biomarkers Prev, 9, 1335-41.
142. Nomura, A. M.: Body size and prostate cancer.
Epidemiol Rev, 23, 126-31 (2001)
143. Lagiou, P., L. B. Signorello, D. Trichopoulos, A.
Tzonou, A. Trichopoulou & C. S. Mantzoros: Leptin in
relation to prostate cancer and benign prostatic hyperplasia.
Int J Cancer, 76, 25-8 (1998)
144. Hsing, A. W., S. Chua, Jr., Y. T. Gao, E. Gentzschein,
L. Chang, J. Deng & F. Z. Stanczyk: Prostate cancer risk
and serum levels of insulin and leptin: a population-based
study. J Natl Cancer Inst, 93, 783-9. (2001)
145. Stattin, P., S. Soderberg, G. Hallmans, A. Bylund, R.
Kaaks, U. H. Stenman, A. Bergh & T. Olsson: Leptin is
associated with increased prostate cancer risk: a nested
case-referent study. J Clin Endocrinol Metab, 86, 1341-5
146. Chang, S., S. D. Hursting, J. H. Contois, S. S. Strom,
Y. Yamamura, R. J. Babaian, P. Troncoso, P. S. Scardino,
T. M. Wheeler, C. I. Amos & M. R. Spitz: Leptin and
prostate cancer. Prostate, 46, 62-7. (2001)
147. Giovannucci, E., E. B. Rimm, Y. Liu & W. C. Willett:
Height, predictors of C-peptide and cancer risk in men. Int
J Epidemiol, 33, 217-25 (2004)
148. Solano, D. C., M. Sironi, C. Bonfini, S. B. Solerte, S.
Govoni & M. Racchi: Insulin regulates soluble amyloid
precursor protein release via phosphatidyl inositol 3 kinase-
dependent pathway. Faseb J, 14, 1015-22 (2000)
149. Prisco, M., G. Romano, F. Peruzzi, B. Valentinis & R.
Baserga: Insulin and IGF-I receptors signaling in protection
from apoptosis. Horm Metab Res, 31, 80-9 (1999)
150. Christoffersen, C. T., H. Tornqvist, C. J. Vlahos, D.
Bucchini, J. Jami, P. De Meyts & R. L. Joshi: Insulin and
insulin-like growth factor-I receptor mediated differentiation of
3T3-F442A cells into adipocytes: effect of PI 3-kinase
inhibition. Biochem Biophys Res Commun, 246, 426-30 (1998)
151. Qin, K. N. & R. L. Rosenfield: Role of cytochrome
P450c17 in polycystic ovary syndrome. Mol Cell Endocrinol,
145, 111-21 (1998)
152. Pasquali, R., F. Casimirri, R. De Iasio, P. Mesini, S.
Boschi, R. Chierici, R. Flamia, M. Biscotti & V. Vicennati:
Insulin regulates testosterone and sex hormone-binding
globulin concentrations in adult normal weight and obese men.
J Clin Endocrinol Metab, 80, 654-8 (1995)
153. Nestler, J. E.: Regulation of the aromatase activity of
human placental cytotrophoblasts by insulin, insulin-like
growth factor-I, and -II. J Steroid Biochem Mol Biol, 44, 449-
154. Bhatia, B. & C. A. Price: Insulin alters the effects of
follicle stimulating hormone on aromatase in bovine granulosa
cells in vitro. Steroids, 66, 511-9 (2001)
155. Moule, S. K. & R. M. Denton: Multiple signaling
pathways involved in the metabolic effects of insulin. Am J
Cardiol, 80, 41A-49A (1997)
156. Yu, H. & T. Rohan: Role of the insulin-like growth
factor family in cancer development and progression. J
Natl Cancer Inst, 92, 1472-89. (2000)
157. Ho, G. Y., A. Melman, S. M. Liu, M. Li, H. Yu, A.
Negassa, R. D. Burk, A. W. Hsing, R. Ghavamian & S. C.
Chua, Jr.: Polymorphism of the insulin gene is associated with
increased prostate cancer risk. Br J Cancer, 88, 263-9. (2003)
158. Claeys, G. B., A. V. Sarma, R. L. Dunn, K. A. Zuhlke, J.
Beebe-Dimmer, J. E. Montie, K. J. Wojno, D. Schottenfeld &
K. A. Cooney: INSPstI polymorphism and prostate cancer in
African-American men. Prostate, 2, 2 (2005)
159. Neuhausen, S. L., M. L. Slattery, C. P. Garner, Y. C.
Ding, M. Hoffman & A. R. Brothman: Prostate cancer risk and
IRS1, IRS2, IGF1, and INS polymorphisms: Strong
association of IRS1 G972R variant and cancer risk. Prostate,
64, 168-74. (2005)
160. Li, L., M. S. Cicek, G. Casey & J. S. Witte: No
association between genetic polymorphisms in insulin and
insulin receptor substrate-1 and prostate cancer. Cancer
Epidemiol Biomarkers Prev, 14, 2462-3 (2005)
161. Ribeiro, R., A. Vasconcelos, S. Costa, D. Pinto, A.
Morais, J. Oliveira, F. Lobo, C. Lopes & R. Medeiros:
Overexpressing leptin genetic polymorphism (-2548 G/A) is
associated with susceptibility to prostate cancer and risk of
advanced disease. Prostate, 59, 268-74 (2004)
162. Kote-Jarai, Z., R. Singh, F. Durocher, D. Easton, S. M.
Edwards, A. Ardern-Jones, D. P. Dearnaley, R. Houlston, R.
Kirby & R. Eeles: Association between leptin receptor gene
polymorphisms and early-onset prostate cancer. BJU Int, 92,
163. Chan, J. M., M. J. Stampfer, J. Ma, P. Gann, J. M.
Gaziano, M. Pollak & E. Giovannucci: Insulin-like growth
factor-I (IGF-I) and IGF binding protein-3 as predictors of
advanced-stage prostate cancer. J Natl Cancer Inst, 94, 1099-
164. LeRoith, D. & C. T. Roberts, Jr.: The insulin-like growth
factor system and cancer. Cancer Lett, 195, 127-37. (2003)
165. Woodson, K., J. A. Tangrea, M. Pollak, T. D. Copeland,
P. R. Taylor, J. Virtamo & D. Albanes: Serum insulin-like
growth factor I: tumor marker or etiologic factor? A
prospective study of prostate cancer among Finnish men.
Cancer Res, 63, 3991-4 (2003)
166. Stattin, P., S. Rinaldi, C. Biessy, U. H. Stenman, G.
Hallmans & R. Kaaks: High levels of circulating insulin-like
growth factor-I increase prostate cancer risk: a prospective
study in a population-based nonscreened cohort. J Clin Oncol,
22, 3104-12. (2004)
167. Chen, C., S. K. Lewis, L. Voigt, A. Fitzpatrick, S. R.
Plymate & N. S. Weiss: Prostate carcinoma incidence in
relation to prediagnostic circulating levels of insulin-like
growth factor I, insulin-like growth factor binding protein 3,
and insulin. Cancer, 103, 76-84. (2005)
168. Chokkalingam, A. P., M. Pollak, C. M. Fillmore, Y. T.
Gao, F. Z. Stanczyk, J. Deng, I. A. Sesterhenn, F. K. Mostofi,
T. R. Fears, M. P. Madigan, R. G. Ziegler, J. F. Fraumeni, Jr.
& A. W. Hsing: Insulin-like growth factors and prostate
cancer: a population-based case-control study in China.
Cancer Epidemiol Biomarkers Prev, 10, 421-7 (2001)
169. Friedrichsen, D. M., S. Hawley, J. Shu, M. Humphrey, L.
Sabacan, L. Iwasaki, R. Etzioni, E. A. Ostrander & J. L.
Stanford: IGF-I and IGFBP-3 polymorphisms and risk of
prostate cancer. Prostate, 30, 30 (2005)
170. Schildkraut, J. M., W. Demark-Wahnefried, R. M.
Wenham, J. Grubber, A. S. Jeffreys, S. C. Grambow, J. R.
Marks, P. G. Moorman, C. Hoyo, S. Ali & P. J. Walther: IGF1
Hormone-related genes and prostate cancer
(CA)19 repeat and IGFBP3 -202 A/C genotypes and the risk
of prostate cancer in Black and White men. Cancer Epidemiol
Biomarkers Prev, 14, 403-8. (2005)
171. Tsuchiya, N., L. Wang, Y. Horikawa, T. Inoue, H.
Kakinuma, S. Matsuura, K. Sato, O. Ogawa, T. Kato & T.
Habuchi: CA repeat polymorphism in the insulin-like growth
factor-I gene is associated with increased risk of prostate
cancer and benign prostatic hyperplasia. Int J Oncol, 26, 225-
172. Li, L., M. S. Cicek, G. Casey & J. S. Witte: No
association between genetic polymorphisms in IGF-I and
IGFBP-3 and prostate cancer. Cancer Epidemiol Biomarkers
Prev, 13, 497-8. (2004)
173. Lai, M. T., R. H. Chen, F. J. Tsai, L. Wan & W. C. Chen:
Glutathione S-transferase M1 gene but not insulin-like growth
factor-2 gene or epidermal growth factor gene is associated
with prostate cancer. Urol Oncol, 23, 225-9 (2005)
174. Wang, L., T. Habuchi, N. Tsuchiya, K. Mitsumori, C.
Ohyama, K. Sato, H. Kinoshita, T. Kamoto, A. Nakamura, O.
Ogawa & T. Kato: Insulin-like growth factor-binding protein-3
gene -202 A/C polymorphism is correlated with advanced
disease status in prostate cancer. Cancer Res, 63, 4407-11.
175. Blutt, S. E. & N. L. Weigel: Vitamin D and prostate
cancer. Proc Soc Exp Biol Med, 221, 89-98 (1999)
176. Getzenberg, R. H., B. W. Light, P. E. Lapco, B. R.
Konety, A. K. Nangia, J. S. Acierno, R. Dhir, Z. Shurin, R. S.
Day, D. L. Trump & C. S. Johnson: Vitamin D inhibition of
prostate adenocarcinoma growth and metastasis in the
Dunning rat prostate model system. Urology, 50, 999-1006
177. Beer, T. M.: ASCENT: the androgen-independent
prostate cancer study of calcitriol enhancing taxotere. BJU Int,
96, 508-13 (2005)
178. Taylor, J. A., A. Hirvonen, M. Watson, G. Pittman, J. L.
Mohler & D. A. Bell: Association of prostate cancer with
vitamin D receptor gene polymorphism. Cancer Res, 56, 4108-
179. Ingles, S. A., G. A. Coetzee, R. K. Ross, B. E. Henderson,
L. N. Kolonel, L. Crocitto, W. Wang & R. W. Haile:
Association of prostate cancer with vitamin D receptor
haplotypes in African-Americans. Cancer Res, 58, 1620-3.
180. Ma, J., M. J. Stampfer, P. H. Gann, H. L. Hough, E.
Giovannucci, K. T. Kelsey, C. H. Hennekens & D. J. Hunter:
Vitamin D receptor polymorphisms, circulating vitamin D
metabolites, and risk of prostate cancer in United States
physicians. Cancer Epidemiol Biomarkers Prev, 7, 385-90.
181. Correa-Cerro, L., P. Berthon, J. Haussler, S. Bochum, E.
Drelon, P. Mangin, G. Fournier, T. Paiss, O. Cussenot & W.
Vogel: Vitamin D receptor polymorphisms as markers in
prostate cancer. Hum Genet, 105, 281-7. (1999)
182. Furuya, Y., K. Akakura, M. Masai & H. Ito: Vitamin
D receptor gene polymorphism in Japanese patients with
prostate cancer. Endocr J, 46, 467-70. (1999)
183. Watanabe, M., K. Fukutome, M. Murata, H. Uemura,
Y. Kubota, J. Kawamura & R. Yatani: Significance of
vitamin D receptor gene polymorphism for prostate cancer
risk in Japanese. Anticancer Res, 19, 4511-4. (1999)
184. Habuchi, T., T. Suzuki, R. Sasaki, L. Wang, K. Sato,
S. Satoh, T. Akao, N. Tsuchiya, N. Shimoda, Y. Wada, A.
Koizumi, J. Chihara, O. Ogawa & T. Kato: Association of
vitamin D receptor gene polymorphism with prostate
cancer and benign prostatic hyperplasia in a Japanese
population. Cancer Res, 60, 305-8. (2000)
185. Blazer, D. G., 3rd, D. M. Umbach, R. M. Bostick & J.
A. Taylor: Vitamin D receptor polymorphisms and prostate
cancer. Mol Carcinog, 27, 18-23. (2000)
186. Chokkalingam, A. P., K. A. McGlynn, Y. T. Gao, M.
Pollak, J. Deng, I. A. Sesterhenn, F. K. Mostofi, J. F.
Fraumeni, Jr. & A. W. Hsing: Vitamin D receptor gene
polymorphisms, insulin-like growth factors, and prostate
cancer risk: a population-based case-control study in China.
Cancer Res, 61, 4333-6. (2001)
187. Gsur, A., S. Madersbacher, G. Haidinger, G. Schatzl,
M. Marberger, C. Vutuc & M. Micksche: Vitamin D
receptor gene polymorphism and prostate cancer risk.
Prostate, 51, 30-4. (2002)
188. Hamasaki, T., H. Inatomi, T. Katoh, T. Ikuyama & T.
Matsumoto: Significance of vitamin D receptor gene
polymorphism for risk and disease severity of prostate
cancer and benign prostatic hyperplasia in Japanese. Urol
Int, 68, 226-31. (2002)
189. Medeiros, R., A. Morais, A. Vasconcelos, S. Costa, D.
Pinto, J. Oliveira & C. Lopes: The role of vitamin D
receptor gene polymorphisms in the susceptibility to
prostate cancer of a southern European population. J Hum
Genet, 47, 413-8. (2002)
190. Suzuki, K., H. Matsui, N. Ohtake, S. Nakata, T. Takei,
H. Koike, H. Nakazato, H. Okugi, M. Hasumi, Y. Fukabori,
K. Kurokawa & H. Yamanaka: Vitamin D receptor gene
polymorphism in familial prostate cancer in a Japanese
population. Int J Urol, 10, 261-6. (2003)
191. Maistro, S., I. Snitcovsky, A. S. Sarkis, I. A. da Silva
& M. M. Brentani: Vitamin D receptor polymorphisms and
prostate cancer risk in Brazilian men. Int J Biol Markers,
19, 245-9. (2004)
192. Oakley-Girvan, I., D. Feldman, T. R. Eccleshall, R. P.
Gallagher, A. H. Wu, L. N. Kolonel, J. Halpern, R. R.
Balise, D. W. West, R. S. Paffenbarger, Jr. & A. S.
Whittemore: Risk of early-onset prostate cancer in relation
to germ line polymorphisms of the vitamin D receptor.
Cancer Epidemiol Biomarkers Prev, 13, 1325-30. (2004)
193. Cheteri, M. B., J. L. Stanford, D. M. Friedrichsen, M.
A. Peters, L. Iwasaki, M. C. Langlois, Z. Feng & E. A.
Ostrander: Vitamin D receptor gene polymorphisms and
prostate cancer risk. Prostate, 59, 409-18. (2004)
194. Huang, S. P., Y. H. Chou, W. S. Wayne Chang, M. T.
Wu, Y. Y. Chen, C. C. Yu, T. T. Wu, Y. H. Lee, J. K.
Huang, W. J. Wu & C. H. Huang: Association between
vitamin D receptor polymorphisms and prostate cancer risk
in a Taiwanese population. Cancer Lett, 207, 69-77. (2004)
195. Mishra, D. K., H. K. Bid, D. S. Srivastava, A.
Mandhani & R. D. Mittal: Association of vitamin D
receptor gene polymorphism and risk of prostate cancer in
India. Urol Int, 74, 315-8. (2005)
196. Hayes, V. M., G. Severi, E. J. Padilla, S. A. Eggleton,
M. C. Southey, R. L. Sutherland, J. L. Hopper & G. G.
Giles: Genetic variants in the vitamin D receptor gene and
prostate cancer risk. Cancer Epidemiol Biomarkers Prev,
14, 997-9. (2005)
197. Ntais, C., A. Polycarpou & J. P. Ioannidis: Vitamin D
receptor gene polymorphisms and risk of prostate cancer: a
Hormone-related genes and prostate cancer
meta-analysis. Cancer Epidemiol Biomarkers Prev, 12,
198. Farnsworth, W. E., W. R. Slaunwhite, Jr., M. Sharma,
F. Oseko, J. R. Brown, M. J. Gonder & R. Cartagena:
Interaction of prolactin and testosterone in the human
prostate. Urol Res, 9, 79-88 (1981)
199. Stattin, P., S. Rinaldi, U. H. Stenman, E. Riboli, G.
Hallmans, A. Bergh & R. Kaaks: Plasma prolactin and
prostate cancer risk: A prospective study. Int J Cancer, 92,
200. Henderson, B. E., L. Bernstein, R. K. Ross, R. H.
Depue & H. L. Judd: The early in utero oestrogen and
testosterone environment of blacks and whites: potential
effects on male offspring. Br J Cancer, 57, 216-8 (1988)
201. Wacholder, S., S. Chanock, M. Garcia-Closas, L. El
Ghormli & N. Rothman: Assessing the probability that a
positive report is false: an approach for molecular
epidemiology studies. J Natl Cancer Inst, 96, 434-42
202. Ioannidis, J. P., M. Gwinn, J. Little, J. P. Higgins, J. L.
Bernstein, P. Boffetta, M. Bondy, M. S. Bray, P. E.
Brenchley, P. A. Buffler, J. P. Casas, A. P. Chokkalingam,
J. Danesh, G. Davey-Smith, S. Dolan, R. Duncan, N. A.
Gruis, P. Hartge, M. Hashibe, D. J. Hunter, M.-R. Jarvelin,
B. Malmer, D. M. Maraganore, J. A. Newton-Bishop, T. R.
O'Brien, G. Petersen, E. Riboli, G. Salanti, D. Seminara, L.
Smeeth, E. Taioli, N. Timpson, A. G. Uitterlinden, P.
Vineis, N. Wareham, D. M. Winn, R. Zimmern & M. J.
Khoury: A road map for efficient and reliable human
genome epidemiology. Nat Genet, 38, 3-5 (2006)
203. Morton, L. M., T. Zheng, T. R. Holford, E. A. Holly,
B. C. Chiu, A. S. Costantini, E. Stagnaro, E. V. Willett, L.
Dal Maso, D. Serraino, E. T. Chang, W. Cozen, S. Davis,
R. K. Severson, L. Bernstein, S. T. Mayne, F. R. Dee, J. R.
Cerhan & P. Hartge: Alcohol consumption and risk of non-
Hodgkin lymphoma: a pooled analysis. Lancet Oncol, 6,
204. Wacholder, S., N. Rothman & N. Caporaso:
Counterpoint: bias from population stratification is not a
major threat to the validity of conclusions from
epidemiological studies of common polymorphisms and
cancer. Cancer Epidemiol Biomarkers Prev, 11, 513-20
205. Yang, N., H. Li, L. A. Criswell, P. K. Gregersen, M.
E. Alarcon-Riquelme, R. Kittles, R. Shigeta, G. Silva, P. I.
Patel, J. W. Belmont & M. F. Seldin: Examination of
ancestry and ethnic affiliation using highly informative
diallelic DNA markers: application to diverse and admixed
populations and implications for clinical epidemiology and
forensic medicine. Hum Genet, 118, 382-92 (2005)
206. http://genmapp.org., Gladstone Institute, University of
California, San Francisco
207. Hung, R. J., P. Brennan, C. Malaveille, S. Porru, F.
Donato, P. Boffetta & J. S. Witte: Using hierarchical
modeling in genetic association studies with multiple
markers: application to a case-control study of bladder
cancer. Cancer Epidemiol Biomarkers Prev, 13, 1013-21
208. Hahn, L. W., M. D. Ritchie & J. H. Moore:
Multifactor dimensionality reduction software for detecting
gene-gene and gene-environment
Bioinformatics, 19, 376-82 (2003)
209. Hayes, R. B.: Gene-environment interrelations in
prostate cancer. Epidemiol Rev, 23, 163-7 (2001)
210. Hunter, D. J., E. Riboli, C. A. Haiman, D. Albanes, D.
Altshuler, S. J. Chanock, R. B. Haynes, B. E. Henderson,
R. Kaaks, D. O. Stram, G. Thomas, M. J. Thun, H.
Blanche, J. E. Buring, N. P. Burtt, E. E. Calle, H. Cann, F.
Canzian, Y. C. Chen, G. A. Colditz, D. G. Cox, A. M.
Dunning, H. S. Feigelson, M. L. Freedman, J. M. Gaziano,
E. Giovannucci, S. E. Hankinson, J. N. Hirschhorn, R. N.
Hoover, T. Key, L. N. Kolonel, P. Kraft, L. Le Marchand,
S. Liu, J. Ma, S. Melnick, P. Pharaoh, M. C. Pike, C.
Rodriguez, V. W. Setiawan, M. J. Stampfer, E. Trapido, R.
Travis, J. Virtamo, S. Wacholder & W. C. Willett: A
candidate gene approach to searching for low-penetrance
breast and prostate cancer genes. Nat Rev Cancer, 5, 977-
211. Bratt, O., A. Borg, U. Kristoffersson, R. Lundgren, Q.
X. Zhang & H. Olsson: CAG repeat length in the androgen
receptor gene is related to age at diagnosis of prostate
cancer and response to endocrine therapy, but not to
prostate cancer risk. Br J Cancer, 81, 672-6. (1999)
212. Krishnaswamy, V., T. Kumarasamy, V. Venkatesan,
S. Shroff, V. R. Jayanth & S. F. Paul: South Indian men
with reduced CAG repeat length in the androgen receptor
gene have an increased risk of prostate cancer. J Hum
213. Loukola, A., M. Chadha, S. G. Penn, D. Rank, D. V.
Conti, D. Thompson, M. Cicek, B. Love, V. Bivolarevic,
Q. Yang, Y. Jiang, D. K. Hanzel, K. Dains, P. L. Paris, G.
Casey & J. S. Witte: Comprehensive evaluation of the
genotypes/haplotypes in CYP17A1,
SRD5A2. Eur J Hum Genet, 12, 321-32. (2004)
Key Words: Neoplasia, Neoplasm, Tumor, Prostate
Cancer, Hormones, Genetic
Send correspondence to: Ann W. Hsing, Ph.D., National
Cancer Institute, EPS-MSC 7234, 6120 Executive Blvd.,
Bethesda MD 20852-7234, Tel: 301-435-3980, Fax: 301-
402-0916, E-mail: email@example.com