The role of androgens and polymorphisms in the androgen receptor in the epidemiology of breast cancer
© BioMed Central Ltd 2003
Published: 1 June 2003
Testosterone binds to the androgen receptor in target tissue to mediate its effects. Variations in testosterone levels and androgen receptor activity may play a role in the etiology of breast cancer. Here, we review the epidemiologic evidence linking endogenous testosterone to breast cancer risk. Paradoxically, results from observational studies that have examined polymorphisms in the androgen receptor suggest that the low-activity androgen receptor increases breast cancer risk. We review the quality of this evidence and conclude with a discussion of how the androgen receptor and testosterone results coincide.
Keywordsandrogen receptor breast cancer CAG polymorphism testosterone
The role of androgens in breast cancer etiology has been a subject of both curiosity and confusion. It is still unclear by which mechanisms testosterone exerts its activity in the female breast, and whether the effects are predominantly proliferative or anti-proliferative on breast cells at physiologic levels. In the present review we evaluate the results from epidemiologic studies on the role of circulating testosterone and a functional polymorphism in the androgen receptor (AR) in breast cancer. We also highlight some of the epidemiologic challenges in addressing these questions.
Sources of endogenous testosterone
There are two main sources of androgens in women. Testosterone is produced directly by the ovary and by conversion of the adrenal androgens dehydroepiandrosterone and dehydroepiandrosterone-sulfate into androstenedione, and then further to testosterone in peripheral tissue . In premenopausal women, approximately 25% of circulating testosterone is secreted directly from the adrenal gland and 25% from the ovary, whereas the remaining 50% is produced by peripheral conversion of androstenedione . Testosterone levels vary over the menstrual cycle with peak levels mid-cycle, and diurnally with highest levels in the early morning .
Testosterone and androstenedione are produced by the interstitial cells of the ovarian stroma and may continue to respond to gonadotopins and produce testosterone after the menopause . In normal postmenopausal women the ovarian vein has been observed to have higher concentrations of testosterone than is found in peripheral blood; bilateral oophorectomy results in reductions in testosterone levels by as much as 50% .
Several smaller cross-sectional studies have found lower testosterone levels in postmenopausal than premenopausal women [6–8] or lower levels in perimenopausal than premenopausal women . Large longitudinal studies that have followed women through the menopausal transition have observed either no significant change in testosterone [2, 9] or a 15% decrease in both testosterone and androstenedione at menopause . In one study of women aged 50–89 years testosterone levels were lowest at the time of the menopause, whereas women older than 70 years or more than 20 years postmenopause had levels approximating those of premenopausal women .
In summary, there is increasing evidence that the ovary continues to produce androstenedione and testosterone in healthy postmenopausal women. Levels may either remain the same or decrease slightly at menopause. However, women with bilateral oophorectomy may be androgen deficient.
Testosterone and breast cancer risk
Prospective studies that examined the association between testosterone and breast cancer
Data from eight prospective cohort studies have been reported on the association between endogenous testosterone levels and breast cancer risk using testosterone measured from blood samples gathered at baseline from postmenopausal women [12–19]. Six of these studies were nested case–control studies [12, 14–18]; one was a case–cohort study  and one a full cohort study . Only one of these studies reported results for premenopausal women .
Six of the eight studies reported a statistically significant increase in postmenopausal breast cancer risk with increasing levels of endogenous testosterone [14–19]. A recently conducted pooled analysis  of these eight prospective studies estimated that the relative risk for breast cancer in women whose levels of testosterone were in the top quintile as compared with women in the bottom quintile was 2.22 (95% confidence interval 1.59–3.10). A statistically significant dose–response relationship was also observed (P for trend < 0.001) . Two of the studies also reported statistically significantly increasing breast cancer risk with increasing levels of free testosterone [15, 19], a measure of bioavailable testosterone.
The study of premenopausal women  found no statistically significant differences between cases and noncases in mean levels in either premenopausal or postmenopausal women, but the sample size was small (premenopausal women: 17 cases, 67 controls; postmenopausal women: 22 cases, 88 controls).
Can the observed association between testosterone levels and breast cancer risk be due to bias?
Effects of measurement biases
One limitation of the studies reviewed is that serum testosterone may not be the ideal measure of testosterone. Total testosterone includes both free testosterone and bound testosterone. Furthermore, serum levels do not take into account the peripheral conversion of precursor androgens into testosterone in the breast tissue itself. The effect of this measurement error is most likely to be nondifferential, therefore biasing results toward the null.
The relative risk for breast cancer associated with testosterone levels in postmenopausal women: results from prospective studies
Author, year [reference]
Wysowski, 1987 
Washington County, MD, USA
39 Cases, 155 controls
Race, age, time since last menstrual period
Matching variables only
Garland, 1992 
Rancho Bernardo, CA
15 Cases, 409 at risk
Age, BMI (tertiles), smoking at baseline(Y/N), other hormones4
Dorgan, 1996 
Columbia, MO, USA
71 Cases, 133 controls
Exact age, date (± 1 year) and time of blood draw (± 2 hours)
Years since menopause, height, weight, parity, family history; matched analysis
Study of Hormones and Diet in the Etiology of BreastTumors, Italy
24 Cases,87 controls
Recruitment center, recruitment date, daylight saving period at time of recruitment, location of freezer storage (freezer and level)
Age at menarche, age at first childbirth, number of births, age at menopause, weight, height, BMI, waist:hip ratio, other hormones, matched analysis
Thomas, 1997 
61 Cases, 179 controls
Age (± 2 years), date of blood
Age at menarche, parity, number of years postmenopausal, BMI, estradiol and SHBG; matched analysis
Zeleniuch-Jocquotte, 1997 
NYU Women's Health Study, USA
85 Cases, 163 controls
Age at enrolment (± 6 months), date of initial blood donation (± 3 months), menopausal status
BMI, age at menarche, parity, age at first full-term pregnancy, age at menopause, family history, history of benign breast condition, history of oophorectomy, lifetime months of lactation, smoking; matched analysis
Hankinson, 1998 
Nurses Health Study, USA
147 Cases, 299 controls
Age (± 2 years), month of collection, time of day that blood was drawn (± 2 hours), fasting status
BMI (at age 18, quartiles), family history, age at menarche(quartiles), parity/age at 1st birth, age at menopause(quartiles); matched analysis
Cauley, 1999 
Study of Osteoporotic Fractures, USA
97 Cases, 250 controls
Age, BMI, age at menarche, first birth, and menopause, surgical menopause (Y/N), nulliparity (Y/N), family history, past estrogen use (Y/N)4, walking for exercise (Y/N), alcohol consumption(g/d quintiles)
The consideration of time of day that blood was drawn and fasting status can help to avoid the biases due to using a single hormone measurement. To avoid this bias, three of the studies either matched with respect to time of blood draw [14, 18] or restricted individuals to having their blood drawn in the morning . Because the effect of these sporadic variations would be to bias the results toward the null, this may help to explain one of the null associations observed .
The studies that observed an association between testosterone and breast cancer risk attempted to reduce measurement bias due to degradation by matching cases to controls on the date of blood draw [14–18] and storage conditions such as sample location/shelf in the freezer . This was not done in the studies reporting no association between testosterone and breast cancer risk [12, 13] or in one of the positive studies .
Laboratory assay variation would also most likely be non-differential because cases and controls were analyzed concurrently in these studies. The intra-assay and inter-assay coefficients of variation in these studies were rather good, ranging from 4% to 14%. However, the coefficient of variation was not reported in one of the null studies .
Thus, although there may be some attenuation in effect estimates in all of the studies, it is not clear whether measurement bias due to degradation can explain the discrepancies between the two null studies and the positive studies.
If breast cancer development increases testosterone levels, then studies that included individuals diagnosed shortly after baseline hormone measurement may have artificially elevated estimates of the risk for breast cancer associated with testosterone levels. Two of the positive studies and both of the null studies excluded those who were diagnosed 6–24 months after baseline [12–14, 17]. However, the study with the most conservative cut-point of 24 months  reported a significant positive association between testosterone levels and breast cancer risk. Thus, although it is possible that temporal bias played a role in the four positive studies with no exclusions, this latter study suggests that temporal bias cannot explain the association between testosterone and breast cancer risk.
Effects of confounding
Lack of control for body mass index (BMI) or age at menopause could result in a positive bias away from the null. All of the studies that reported a significant association between testosterone levels and breast cancer risk included either BMI or height and weight as covariates in the statistical model. All but one of the null studies  considered either the amount of time menopausal [12, 14, 16] or age at menopause [15, 17–19] as a covariate to control for the effects of menopause on testosterone levels. Thus, it is unlikely that confounding by these variables can explain the associations observed between testosterone levels and breast cancer risk.
All of the prospective studies that examined the testosterone–breast cancer association were conducted using cohorts from Caucasian populations. Only two studies [15, 16] were conducted outside the USA, one in Italy  and one on the island of Guernsey . It is therefore unlikely that differences in the populations studied can explain the discrepant results between studies. There are, as far as we know, no prospective data from nonwhite populations.
Studies of testosterone measured after diagnosis that examined the testosterone–breast cancer association
The relative risk of breast cancer associated with testosterone levels: results from case–control studies
Author, year [reference]
Secreto, 1984 2
Premenopausal women in Milan
Secreto, 1989 2
Women in Milan age 30–49 years
Secreto, 1991 3
Postmenopausal women in Milan<69 years of age
Lipworth, 1996 5
Postmenopausal women from Sweden
Mean levels of testosterone in breast cancer cases and controls
Author, year [reference]
Secreto, 1983 
Secreto, 1983 
Secreto, 1984 
Hill, 1985 
Adlercreutz, 1989 
Both retrospective and prospective studies have reported statistically significant associations between increased levels of testosterone and increased breast cancer risk. These associations are unlikely to be due to measurement biases, the influence of disease, or lack of adjustment for the confounding effects of BMI or age at menopause.
Androgen receptor, the AR-CAG repeat, and breast cancer risk
The main receptor for testosterone is the AR. A functional polymorphism in the AR gene has been examined in female breast cancer, and the literature is reviewed to shed light on the possible mechanisms by which testosterone may affect breast cancer risk.
Androgen receptor protein and breast cancer
The AR is expressed in the majority of breast cancers [29–35]. Several studies have been conducted to examine the effects of androgens on the growth of AR-positive breast cancer cell lines. These studies have reported both inhibitory [36, 37] and stimulatory [38, 39] effects. These divergent effects have been observed to be specific to the cell line under study .
To our knowledge, the only in vivo study of the effect of testosterone on breast cell proliferation was conducted in rats and showed that treatment with testosterone results in both tumor regression and a reduction in estrogen receptor expression . However, it is unclear whether the testosterone levels used represent physiologic doses. No in vivo or epidemiologic studies have examined the association between serum or tissue testosterone levels and breast cell proliferation in tumors with varying degrees of AR expression.
In summary, the effects of androgens on breast cancer cell growth are still unclear. In contrast to the epidemiologic observation of a consistent association between serum testosterone levels and increasing breast cancer risk, in vivo studies reported an antiproliferative effect and in vitro studies reported both proliferative and antiproliferative effects.
The androgen receptor gene and a polymorphic CAG repeat
The AR is encoded by a single 90 kilobase gene on the X chromosome (Xq11-q12), which encodes a 11-kilobase mRNA transcript composed of eight exons [42–46]. Epidemiologic evidence for a role of the AR gene in breast cancer was first suggested by studies of male breast cancer patients. A mutation in AR in the DNA-binding domain resulting in an inability to bind androgens was first reported in a pair of brothers with breast cancer . In a study of 13 male breast cancer patients, one was observed to carry a similar mutation . In another small study of 11 male breast cancer patients , this mutation was not observed. These results suggested that the mutation may play a role in the development of breast cancer in some males.
Within the first exon of AR lies a polymorphic CAG repeat that encodes a polyglutamine tract of variable length. The normal size range of these repeats is between 6 and 39 repeats [50, 51]. Between 40 and 66 repeats have been observed in patients with a rare, neurodegenerative disorder called spinal and bulbar muscular atrophy , which is characterized by androgen insensitivity with gynecomastia, testicular atrophy, oligospermia, azoospermia, and elevated serum gonadotropins.
AR-CAG repeat length and androgen receptor activity
Several studies have observed an association between increasing AR-CAG repeat length and a linear decrease in AR transactivation activity [53–56]. Consistent with this, male carriers of the short AR-CAG repeat length are at increased risk for prostate cancer [51, 57–62].
AR-CAG repeat length and breast cancer
Relative risk for breast cancer associated with the AR-CAG repeat
Author, year [reference]
RR (95% CI)
Rebbeck, 1999 
Multi-institutional study of BRCA1 mutation carriers ascertained through families with a history of breast and/or ovarian cancer between 1978 and 1997
Spurdle, 1999 
Early onset breast cancer (<40 years) and age matched controls from Australia
Age, country of birth, state, education, marital status, number of live births, height, weight1 year ago, age at menarche, oral contraceptive use, family history, estrogen receptor polymorphism, mother's country of birth, father's country of birth
Dunning, 1999 
Cases from East Anglian region of the UK and random controls from the EPIC cohort
Giguere, 2001 
Incident cases from Quebec city and age and area of residency matched controls
Kadouri, 2001 
Affected and unaffected BRCA1/2 carriers from two genetics clinics: one in Jerusalem, Israel, and the other in London, UK
Haiman, 2002 
Cases and controls from the Nurses' Health Study and controls matched on year of birth, menopausal status, postmenopausal hormone use, and time of day, month, and fasting status at blood draw
Age at menarche, parity, age at first birth, BMI at age 18 years, weight gain since age 8, benign breast disease, first degree family history, duration of postmenopausal hormone use; matched analysis
Suter, 2003 
Cases (<45 years) identified through the Cancer Surveillance System of Western Washington and frequency-matched controls on 5-year age group and reference year
Age at reference and reference year
The three studies that reported a significant association between long AR-CAG repeat and breast cancer risk [63, 66, 68] included both premenopausal and postmenopausal women. One study stratified with respect to menopausal status and found that the significant association with the long AR-CAG repeat was observed only in postmenopausal women (odds ratio 3.22, 95% confidence interval 1.54–6.75) and not in premenopausal women (odds ratio 1.03, 95% confidence interval 0.43–2.48). If this effect modification is true then it may explain, at least in part, the nonsignificant results in the studies restricted to women aged under 40 years .
Issues with the studies of AR-CAG repeat length and breast cancer risk
The gene for the AR lies on the X chromosome, and therefore women carry two alleles whereas men carry only a single allele. In general, normal women are a mosaic, with one allele randomly expressed in each cell. A recent study  reported that 13% of young (27–45 years old) breast cancer cases exhibited preferential activation of one of the AR alleles as measured by genotyping of peripheral blood DNA, but there was no preference toward the allele with the longer or shorter CAG repeat. Analyses of the AR in women that only consider the length of the CAG repeat on one allele assume that this is the active allele in the breast tissue. Analyses that use the average of the CAG repeat lengths or the sum of the repeats consider the contributions of both alleles; however, if only one allele is preferentially expressed then this would result in misclassification. There is a high rate of heterozygosity in the AR-CAG repeat length, and therefore this is likely to be a major misclassification problem, which should bias the results toward the null. Genotyping methods can be optimized to detect better whether there is a preferentially active AR allele by either genotyping tumor tissue or serum DNA using methylation sensitive enzymes .
The studies conducted thus far suggest that the long AR-CAG repeat (less active AR) may be associated with increased breast cancer risk in women who are postmenopausal, have a first-degree family history of breast cancer or who have a known BRCA1 mutation. The location of the AR gene on the X chromosome means that results from epidemiologic studies will be biased toward the null as long as we do not know which allele is expressed.
If the long AR-CAG repeat (less active AR) is associated with increased breast cancer risk in postmenopausal women, then how do these results coincide with results showing that increased testosterone levels increase postmenopausal breast cancer risk?
One hypothesis to explain this apparent paradox is that the less active AR may be involved in a physiologic feedback associated with increased circulating testosterone. However, the only data available discount this hypothesis. Two studies have examined the association between the AR-CAG repeat length and circulating testosterone levels in normal women [68, 73]. AR-CAG repeat length was inversely associated with testosterone levels. In other words, the less active AR was associated with lower circulating testosterone levels, and the results were statistically significant both in a study of premenopausal women  and in a study of postmenopausal women .
If the AR is not involved in a feedback mechanism to influence testosterone levels in postmenopausal women, then it is possible that the effect of testosterone on the breast epithelium does not act through binding to the AR. Testosterone may exert its effect on breast tissue through conversion of testosterone to estrone, which is then aromatized into estradiol in adipose tissue, and the increased estradiol levels may result in increased breast cell proliferation and breast cancer risk.
Testosterone may also exert an indirect effect on breast cancer proliferation by sequestering sex hormone binding globulin, leaving more estradiol in the non-protein-bound state and able to act on breast tissue [25, 74]. Approximately 66% of total testosterone is bound to sex hormone binding globulin, 31% is bound to albumin, and 2% is bound to cortisol binding protein . Two of the studies suggesting an association between testosterone and breast cancer [16, 17] reported that this association disappeared when adjusting for estradiol levels. However, in the pooled analysis  the significant association between testosterone and breast cancer risk remained after adjustment for estradiol .
Finally, it is possible that further studies will show that AR-CAG repeat length is not linked to breast cancer risk.
Prospectively conducted epidemiologic studies have found that increased levels of serum testosterone are associated with an increase in postmenopausal breast cancer risk. However, a number of questions remain. Several lines of evidence suggest a role of AR in breast cancer risk, and sparse epidemiologic data suggest that a long AR-CAG repeat yielding a less active AR may be associated with increased risk. There still remain a number of questions on how testosterone increases breast cancer risk. Although in vitro studies report both proliferative and antiproliferative effects of testosterone on the growth of various breast cancer cell lines, we still need to further understand under which in vivo circumstances does testosterone exert these effects. Finally, we do not know whether androgens affect breast cancer risk in premenopausal women. Further analyses of the role of AR-CAG repeat length and breast cancer using genotyping methods that assess which allele is the active AR allele are clearly needed. Additional data are also needed to help elucidate the apparent paradox between the AR-CAG repeat length, testosterone levels, and breast cancer risk.
= androgen receptor
= body mass index
= cytosine adenine guanine
= guanine guanine cytosine.
This research (EOL) was supported by funds from the California Breast Cancer Research Program, Grant Number 8GB-0010.
- Norman AW, Litwack G: Hormones. 1987, San Diego, CA: Academic PressGoogle Scholar
- Longcope C, Franz C, Morello C, Baker R, Johnston CC: Steroid and gonadotropin levels in women during the perimenopausal years. Maturitas. 1986, 8: 189-196.View ArticlePubMedGoogle Scholar
- Abraham GE: Ovarian and adrenal contribution to peripheral androgens during the menstrual cycle. J Clin Endocrinol Metab. 1974, 39: 340-346.View ArticlePubMedGoogle Scholar
- Adashi EY: The climacteric ovary as a functional gonadotropin-driven androgen-producing gland. Fertil Steril. 1994, 62: 20-27.View ArticlePubMedGoogle Scholar
- Judd HL, Lucas WE, Yen SS: Effect of oophorectomy on circulating testosterone and androstenedione levels in patients with endometrial cancer. Am J Obstet Gynecol. 1974, 118: 793-798.View ArticlePubMedGoogle Scholar
- Zumoff B, Strain GW, Miller LK, Rosner W: Twenty-four-hour mean plasma testosterone concentration declines with age in normal premenopausal women. J Clin Endocrinol Metab. 1995, 80: 1429-1430.PubMedGoogle Scholar
- Bancroft J, Cawood EH: Androgens and the menopause: a study of 40–60-year-old women. Clin Endocrinol (Oxf). 1996, 45: 577-587. 10.1046/j.1365-2265.1996.00846.x.View ArticleGoogle Scholar
- Labrie F, Belanger A, Cusan L, Gomez JL, Candas B: Marked decline in serum concentrations of adrenal C19 sex steroid precursors and conjugated androgen metabolites during aging. J Clin Endocrinol Metab. 1997, 82: 2396-2402.View ArticlePubMedGoogle Scholar
- Burger HG, Dudley EC, Cui J, Dennerstein L, Hopper JL: A prospective longitudinal study of serum testosterone, dehydroepiandrosterone sulfate, and sex hormone-binding globulin levels through the menopause transition. J Clin Endocrinol Metab. 2000, 85: 2832-2838.PubMedGoogle Scholar
- Rannevik G, Jeppsson S, Johnell O, Bjerre B, Laurell-Borulf Y, Svanberg L: A longitudinal study of the perimenopausal transition: altered profiles of steroid and pituitary hormones, SHBG and bone mineral density. Maturitas. 1995, 21: 103-113. 10.1016/0378-5122(94)00869-9.View ArticlePubMedGoogle Scholar
- Laughlin GA, Barrett-Connor E, Kritz-Silverstein D, von Muhlen D: Hysterectomy, oophorectomy, and endogenous sex hormone levels in older women: the Rancho Bernardo Study. J Clin Endocrinol Metab. 2000, 85: 645-651.PubMedGoogle Scholar
- Wysowski DK, Comstock GW, Helsing KJ, Lau HL: Sex hormone levels in serum in relation to the development of breast cancer. Am J Epidemiol. 1987, 125: 791-799.PubMedGoogle Scholar
- Garland CF, Friedlander NJ, Barrett-Connor E, Khaw KT: Sex hormones and postmenopausal breast cancer: a prospective study in an adult community. Am J Epidemiol. 1992, 135: 1220-1230.PubMedGoogle Scholar
- Dorgan JF, Longcope C, Stephenson HE, Falk RT, Miller R, Franz C, Kahle L, Campbell WS, Tangrea JA, Schatzkin A: Relation of prediagnostic serum estrogen and androgen levels to breast cancer risk. Cancer Epidemiol Biomarkers Prev. 1996, 5: 533-539.PubMedGoogle Scholar
- Berrino F, Muti P, Micheli A, Bolelli G, Krogh V, Sciajno R, Pisani P, Panico S, Secreto G: Serum sex hormone levels after menopause and subsequent breast cancer. J Natl Cancer Inst. 1996, 88: 291-296.View ArticlePubMedGoogle Scholar
- Thomas HV, Key TJ, Allen DS, Moore JW, Dowsett M, Fentiman IS, Wang DY: A prospective study of endogenous serum hormone concentrations and breast cancer risk in postmenopausal women on the island of Guernsey. Br J Cancer. 1997, 76: 401-405.View ArticlePubMedPubMed CentralGoogle Scholar
- Zeleniuch-Jacquotte A, Bruning PF, Bonfrer JM, Koenig KL, Shore RE, Kim MY, Pasternack BS, Toniolo P: Relation of serum levels of testosterone and dehydroepiandrosterone sulfate to risk of breast cancer in postmenopausal women. Am J Epidemiol. 1997, 145: 1030-1038.View ArticlePubMedGoogle Scholar
- Hankinson SE, Willett WC, Manson JE, Colditz GA, Hunter DJ, Spiegelman D, Barbieri RL, Speizer FE: Plasma sex steroid hormone levels and risk of breast cancer in postmenopausal women. J Natl Cancer Inst. 1998, 90: 1292-1299. 10.1093/jnci/90.17.1292.View ArticlePubMedGoogle Scholar
- Cauley JA, Lucas FL, Kuller LH, Stone K, Browner W, Cummings SR: Elevated serum estradiol and testosterone concentrations are associated with a high risk for breast cancer: study of Osteoporotic Fractures Research Group. Ann Intern Med. 1999, 130: 270-277.View ArticlePubMedGoogle Scholar
- Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J Natl Cancer Inst. 2002, 94: 606-616.
- Secreto G, Recchione C, Cavalleri A, Miraglia M, Dati V: Circulating levels of testosterone, 17 beta-oestradiol, luteinising hormone and prolactin in postmenopausal breast cancer patients. Br J Cancer. 1983, 47: 269-275.View ArticlePubMedPubMed CentralGoogle Scholar
- Hill P, Garbaczewski L, Kasumi F: Plasma testosterone and breast cancer. Eur J Cancer Clin Oncol. 1985, 21: 1265-1266.View ArticlePubMedGoogle Scholar
- Adlercreutz H, Hamalainen E, Gorbach SL, Goldin BR, Woods MN, Dwyer JT: Diet and plasma androgens in postmenopausal vegetarian and omnivorous women and postmenopausal women with breast cancer. Am J Clin Nutr. 1989, 49: 433-442.PubMedGoogle Scholar
- Secreto G, Recchione C, Ballerini P, Callegari L, Cavalleri A, Attili A, Fariselli G, Moglia D, Del Prato I: Accumulation of active androgens in breast cyst fluids. Eur J Cancer. 1991, 27: 44-47.View ArticlePubMedGoogle Scholar
- Lipworth L, Adami HO, Trichopoulos D, Carlstrom K, Mantzoros C: Serum steroid hormone levels, sex hormone-binding globulin, and body mass index in the etiology of postmenopausal breast cancer. Epidemiology. 1996, 7: 96-100.View ArticlePubMedGoogle Scholar
- Secreto G, Fariselli G, Bandieramonte G, Recchione C, Dati V, Di Pietro S: Androgen excretion in women with a family history of breast cancer or with epithelial hyperplasia or cancer of the breast. Eur J Cancer Clin Oncol. 1983, 19: 5-10.View ArticlePubMedGoogle Scholar
- Secreto G, Recchione C, Fariselli G, Di Pietro S: High testosterone and low progesterone circulating levels in premenopausal patients with hyperplasia and cancer of the breast. Cancer Res. 1984, 44: 841-844.PubMedGoogle Scholar
- Secreto G, Toniolo P, Pisani P, Recchione C, Cavalleri A, Fariselli G, Totis A, Di Pietro S, Berrino F: Androgens and breast cancer in premenopausal women. Cancer Res. 1989, 49: 471-476.PubMedGoogle Scholar
- Bryan RM, Mercer RJ, Bennett RC, Rennie GC, Lie TH, Morgan FJ: Androgen receptors in breast cancer. Cancer. 1984, 54: 2436-2440.View ArticlePubMedGoogle Scholar
- Lea OA, Kvinnsland S, Thorsen T: Improved measurement of androgen receptors in human breast cancer. Cancer Res. 1989, 49: 7162-7167.PubMedGoogle Scholar
- Kuenen-Boumeester V, Van der Kwast TH, van Putten WL, Claassen C, van Ooijen B, Henzen-Logmans SC: Immunohistochemical determination of androgen receptors in relation to oestrogen and progesterone receptors in female breast cancer. Int J Cancer. 1992, 52: 581-584.View ArticlePubMedGoogle Scholar
- Soreide JA, Lea OA, Varhaug JE, Skarstein A, Kvinnsland S: Androgen receptors in operable breast cancer: relation to other steroid hormone receptors, correlations to prognostic factors and predictive value for effect of adjuvant tamoxifen treatment. Eur J Surg Oncol. 1992, 18: 112-118.PubMedGoogle Scholar
- Hall RE, Aspinall JO, Horsfall DJ, Birrell SN, Bentel JM, Sutherland RL, Tilley WD: Expression of the androgen receptor and an androgen-responsive protein, apolipoprotein D, in human breast cancer. Br J Cancer. 1996, 74: 1175-1180.View ArticlePubMedPubMed CentralGoogle Scholar
- Bayer-Garner IB, Smoller B: Androgen receptors: a marker to increase sensitivity for identifying breast cancer in skin metastasis of unknown primary site. Mod Pathol. 2000, 13: 119-122.View ArticlePubMedGoogle Scholar
- Brys M, Wojcik M, Romanowicz-Makowska H, Krajewska WM: Androgen receptor status in female breast cancer: RT-PCR and Western blot studies. J Cancer Res Clin Oncol. 2002, 128: 85-90. 10.1007/s004320100294.View ArticlePubMedGoogle Scholar
- Poulin R, Baker D, Labrie F: Androgens inhibit basal and estrogen-induced cell proliferation in the ZR-75-1 human breast cancer cell line. Breast Cancer Res Treat. 1988, 12: 213-225.View ArticlePubMedGoogle Scholar
- Ortmann J, Prifti S, Bohlmann MK, Rehberger-Schneider S, Strowitzki T, Rabe T: Testosterone and 5 alpha-dihydrotestosterone inhibit in vitro growth of human breast cancer cell lines. Gynecol Endocrinol. 2002, 16: 113-120.View ArticlePubMedGoogle Scholar
- Hackenberg R, Hofmann J, Holzel F, Schulz KD: Stimulatory effects of androgen and antiandrogen on the in vitro proliferation of human mammary carcinoma cells. J Cancer Res Clin Oncol. 1988, 114: 593-601.View ArticlePubMedGoogle Scholar
- Marugo M, Bernasconi D, Miglietta L, Fazzuoli L, Ravera F, Cassulo S, Giordano G: Effects of dihydrotestosterone and hydroxyflutamide on androgen receptors in cultured human breast cancer cells (EVSA-T). J Steroid Biochem Mol Biol. 1992, 42: 547-554. 10.1016/0960-0760(92)90268-N.View ArticlePubMedGoogle Scholar
- Birrell SN, Bentel JM, Hickey TE, Ricciardelli C, Weger MA, Horsfall DJ, Tilley WD: Androgens induce divergent proliferative responses in human breast cancer cell lines. J Steroid Biochem Mol Biol. 1995, 52: 459-467. 10.1016/0960-0760(95)00005-K.View ArticlePubMedGoogle Scholar
- Zava DT, McGuire WL: Estrogen receptors in androgen-induced breast tumor regression. Cancer Res. 1977, 37: 1608-1610.PubMedGoogle Scholar
- Chang CS, Kokontis J, Liao ST: Structural analysis of complementary DNA and amino acid sequences of human and rat androgen receptors. Proc Natl Acad Sci U S A. 1988, 85: 7211-7215.View ArticlePubMedPubMed CentralGoogle Scholar
- Lubahn DB, Joseph DR, Sullivan PM, Willard HF, French FS, Wilson EM: Cloning of human androgen receptor complementary DNA and localization to the X chromosome. Science. 1988, 240: 327-330.View ArticlePubMedGoogle Scholar
- Lubahn DB, Brown TR, Simental JA, Higgs HN, Migeon CJ, Wilson EM, French FS: Sequence of the intron/exon junctions of the coding region of the human androgen receptor gene and identification of a point mutation in a family with complete androgen insensitivity. Proc Natl Acad Sci U S A. 1989, 86: 9534-9538.View ArticlePubMedPubMed CentralGoogle Scholar
- Tilley WD, Marcelli M, Wilson JD, McPhaul MJ: Characterization and expression of a cDNA encoding the human androgen receptor. Proc Natl Acad Sci U S A. 1989, 86: 327-331.View ArticlePubMedPubMed CentralGoogle Scholar
- Brown CJ, Goss SJ, Lubahn DB, Joseph DR, Wilson EM, French FS, Willard HF: Androgen receptor locus on the human X chromosome: regional localization to Xq11-12 and description of a DNA polymorphism. Am J Hum Genet. 1989, 44: 264-269.PubMedPubMed CentralGoogle Scholar
- Wooster R, Mangion J, Eeles R, Smith S, Dowsett M, Averill D, Barrett-Lee P, Easton DF, Ponder BA, Stratton MR: A germline mutation in the androgen receptor gene in two brothers with breast cancer and Reifenstein syndrome. Nat Genet. 1992, 2: 132-134.View ArticlePubMedGoogle Scholar
- Lobaccaro JM, Lumbroso S, Belon C, Galtier-Dereure F, Bringer J, Lesimple T, Heron JF, Pujol H, Sultan C: Male breast cancer and the androgen receptor gene. Nat Genet. 1993, 5: 109-110.View ArticlePubMedGoogle Scholar
- Hiort O, Naber SP, Lehners A, Muletta-Feurer S, Sinnecker GH, Zollner A, Komminoth P: The role of androgen receptor gene mutations in male breast carcinoma. J Clin Endocrinol Metab. 1996, 81: 3404-3407.PubMedGoogle Scholar
- Edwards A, Hammond HA, Jin L, Caskey CT, Chakraborty R: Genetic variation at five trimeric and tetrameric tandem repeat loci in four human population groups. Genomics. 1992, 12: 241-253.View ArticlePubMedGoogle Scholar
- Giovannucci E, Stampfer MJ, Krithivas K, Brown M, Dahl D, Brufsky A, Talcott J, Hennekens CH, Kantoff PW: The CAG repeat within the androgen receptor gene and its relationship to prostate cancer. Proc Natl Acad Sci U S A. 1997, 94: 3320-3323. 10.1073/pnas.94.7.3320.View ArticlePubMedPubMed CentralGoogle Scholar
- La Spada AR, Wilson EM, Lubahn DB, Harding AE, Fischbeck KH: Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature. 1991, 352: 77-79. 10.1038/352077a0.View ArticlePubMedGoogle Scholar
- Chamberlain NL, Driver ED, Miesfeld RL: The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Res. 1994, 22: 3181-3186.View ArticlePubMedPubMed CentralGoogle Scholar
- Kazemi-Esfarjani P, Trifiro MA, Pinsky L: Evidence for a repressive function of the long polyglutamine tract in the human androgen receptor: possible pathogenetic relevance for the (CAG)n-expanded neuronopathies. Hum Mol Genet. 1995, 4: 523-527.View ArticlePubMedGoogle Scholar
- Tut TG, Ghadessy FJ, Trifiro MA, Pinsky L, Yong EL: Long polyglutamine tracts in the androgen receptor are associated with reduced trans-activation, impaired sperm production, and male infertility. J Clin Endocrinol Metab. 1997, 82: 3777-3782.PubMedGoogle Scholar
- Irvine RA, Ma H, Yu MC, Ross RK, Stallcup MR, Coetzee GA: Inhibition of p160-mediated coactivation with increasing androgen receptor polyglutamine length. Hum Mol Genet. 2000, 9: 267-274. 10.1093/hmg/9.2.267.View ArticlePubMedGoogle Scholar
- Irvine RA, Yu MC, Ross RK, Coetzee GA: The CAG and GGC microsatellites of the androgen receptor gene are in linkage disequilibrium in men with prostate cancer. Cancer Res. 1995, 55: 1937-1940.PubMedGoogle Scholar
- Ingles SA, Ross RK, Yu MC, Irvine RA, La Pera G, Haile RW, Coetzee GA: Association of prostate cancer risk with genetic polymorphisms in vitamin D receptor and androgen receptor. J Natl Cancer Inst. 1997, 89: 166-170. 10.1093/jnci/89.2.166.View ArticlePubMedGoogle Scholar
- Stanford JL, Just JJ, Gibbs M, Wicklund KG, Neal CL, Blumenstein BA, Ostrander EA: Polymorphic repeats in the androgen receptor gene: molecular markers of prostate cancer risk. Cancer Res. 1997, 57: 1194-1198.PubMedGoogle Scholar
- Hakimi JM, Schoenberg MP, Rondinelli RH, Piantadosi S, Barrack ER: Androgen receptor variants with short glutamine or glycine repeats may identify unique subpopulations of men with prostate cancer. Clin Cancer Res. 1997, 3: 1599-1608.PubMedGoogle Scholar
- Ekman P, Gronberg H, Matsuyama H, Kivineva M, Bergerheim US, Li C: Links between genetic and environmental factors and prostate cancer risk. Prostate. 1999, 39: 262-268. 10.1002/(SICI)1097-0045(19990601)39:4<262::AID-PROS6>3.3.CO;2-G.View ArticlePubMedGoogle Scholar
- Hsing AW, Gao YT, Wu G, Wang X, Deng J, Chen YL, Sesterhenn IA, Mostofi FK, Benichou J, Chang C: Polymorphic CAG and GGN repeat lengths in the androgen receptor gene and prostate cancer risk: a population-based case–control study in China. Cancer Res. 2000, 60: 5111-5116.PubMedGoogle Scholar
- Rebbeck TR, Kantoff PW, Krithivas K, Neuhausen S, Blackwood MA, Godwin AK, Daly MB, Narod SA, Garber JE, Lynch HT, Weber BL, Brown M: Modification of BRCA1-associated breast cancer risk by the polymorphic androgen-receptor CAG repeat. Am J Hum Genet. 1999, 64: 1371-1377. 10.1086/302366.View ArticlePubMedPubMed CentralGoogle Scholar
- Spurdle AB, Dite GS, Chen X, Mayne CJ, Southey MC, Batten LE, Chy H, Trute L, McCredie MR, Giles GG, Armes J, Venter DJ, Hopper JL, Chenevix-Trench G: Androgen receptor exon 1 CAG repeat length and breast cancer in women before age forty years. J Natl Cancer Inst. 1999, 91: 961-966. 10.1093/jnci/91.11.961.View ArticlePubMedGoogle Scholar
- Dunning AM, McBride S, Gregory J, Durocher F, Foster NA, Healey CS, Smith N, Pharoah PD, Luben RN, Easton DF, Ponder BA: No association between androgen or vitamin D receptor gene polymorphisms and risk of breast cancer. Carcinogenesis. 1999, 20: 2131-2135. 10.1093/carcin/20.11.2131.View ArticlePubMedGoogle Scholar
- Giguere Y, Dewailly E, Brisson J, Ayotte P, Laflamme N, Demers A, Forest VI, Dodin S, Robert J, Rousseau F: Short polyglutamine tracts in the androgen receptor are protective against breast cancer in the general population. Cancer Res. 2001, 61: 5869-5874.PubMedGoogle Scholar
- Kadouri L, Easton DF, Edwards S, Hubert A, Kote-Jarai Z, Glaser B, Durocher F, Abeliovich D, Peretz T, Eeles RA: CAG and GGC repeat polymorphisms in the androgen receptor gene and breast cancer susceptibility in BRCA1/2 carriers and non-carriers. Br J Cancer. 2001, 85: 36-40. 10.1054/bjoc.2001.1777.View ArticlePubMedPubMed CentralGoogle Scholar
- Haiman CA, Brown M, Hankinson SE, Spiegelman D, Colditz GA, Willett WC, Kantoff PW, Hunter DJ: The androgen receptor CAG repeat polymorphism and risk of breast cancer in the Nurses' Health Study. Cancer Res. 2002, 62: 1045-1049.PubMedGoogle Scholar
- Suter NM, Malone KE, Daling JR, Doody DR, Ostrander EA: Androgen receptor (CAG)n and (GGC)n polymorphism and breast cancer risk in a population-based case–control study of young women. Cancer Epidemiol Biomarkers Prev. 2003, 12: 127-135.PubMedGoogle Scholar
- Platz EA, Giovannucci E, Dahl DM, Krithivas K, Hennekens CH, Brown M, Stampfer MJ, Kantoff PW: The androgen receptor gene GGN microsatellite and prostate cancer risk. Cancer Epidemiol Biomarkers Prev. 1998, 7: 379-384.PubMedGoogle Scholar
- Chang BL, Zheng SL, Hawkins GA, Isaacs SD, Wiley KE, Turner A, Carpten JD, Bleecker ER, Walsh PC, Trent JM, Meyers DA, Isaacs WB, Xu J: Polymorphic GGC repeats in the androgen receptor gene are associated with hereditary and sporadic prostate cancer risk. Hum Genet. 2002, 110: 122-129. 10.1007/s00439-001-0662-6.View ArticlePubMedGoogle Scholar
- Kristiansen M, Langerod A, Knudsen GP, Weber BL, Borresen-Dale AL, Orstavik KH: High frequency of skewed X inactivation in young breast cancer patients. J Med Genet. 2002, 39: 30-33. 10.1136/jmg.39.1.30.View ArticlePubMedPubMed CentralGoogle Scholar
- Westberg L, Baghaei F, Rosmond R, Hellstrand M, Landen M, Jansson M, Holm G, Bjorntorp P, Eriksson E: Polymorphisms of the androgen receptor gene and the estrogen receptor beta gene are associated with androgen levels in women. J Clin Endocrinol Metab. 2001, 86: 2562-2568.PubMedGoogle Scholar
- Siiteri PK, Hammond GL, Nisker JA: Increased availability of serum estrogens in breast cancer: a new hypothesis. In Hormones and Breast Cancer. Edited by: Pike MC, Siiteri PK and Welsch CW. 1981, New York: Cold Spring Harbor Laboratory, 87-106.Google Scholar
- Dunn JF, Nisula BC, Rodbard D: Transport of steroid hormones: binding of 21 endogenous steroids to both testosterone-binding globulin and corticosteroid-binding globulin in human plasma. J Clin Endocrinol Metab. 1981, 53: 58-68.View ArticlePubMedGoogle Scholar