The androgen receptor CAG repeat: a modifier of carcinogenesis?

https://doi.org/10.1016/S0303-7207(02)00104-1Get rights and content

Abstract

The first exon of the human androgen receptor (AR) contains a translated CAG (poly-glutamine) repeat. The repeat length is polymorphic in the normal population ranging from 8 to 35 repeats. Expansions to over 40 repeats lead to spinal bulbar muscular atrophy (SBMA), a late onset neurodegenerative disease. The repeat is located between the two parts of a bipartite amino-terminal transactivation function and the repeat length, also within in the normal range, is inversely correlated to the transactivation power of the receptor. P160 type co-activators bind more strongly to shorter repeats. A correlation between AR CAG repeat length and total risk, age at diagnosis, recurrence after surgery and aggressive growth has been reported for tumors of classical androgen target tissues. In the prostate, where androgens exert a mitogenic effect, the cancer risk increases with decreasing AR-CAG repeat length. In contrast, in the breast, where the hormone probably acts as anti-mitogen, a higher risk and earlier onset of breast cancer has been reported for carriers of BRCA1 mutations who also have long CAG repeats in the receptor gene. Somatic alterations during carcinogenesis appear to be frequent in endometrial and in colon cancer. In the endometrium the AR CAG repeat prevalently undergoes expansions consistent with the putative protective function of androgens in this tissue. Frequent repeat reductions during colon carcinogenesis would be consistent with a mitogenic effect of androgens. Analysis of AR protein expression by Western blot reveals expression of the AR in healthy and neoplastic colon tissues. Normal mucosa of the colon expresses both AR-isoforms of 110 and 87 kDa, while the tumor samples have lost the expression of the 110-kDa isoform. The 87-kDa isoform is devoid of the amino-terminal portion of the receptor molecule that also contains the poly-glutamine tract. The temporal and causal relation between isoform switch and somatic repeat reductions during colon carcinogenesis is as yet unclear, but the two events could both enhance p160 mediated androgen signaling. The recent finding that smad3 interacts with the AR in a way similar to p160 links the AR to TGFβ signaling. Interruption of this signaling pathway is a frequent event in colon carcinogenesis.

Introduction

The androgen receptor (AR) belongs to the superfamily of nuclear receptors composed of zinc-finger type transcription factors (Tilley et al., 1989). Like most of the members of this superfamily the transactivation function of the AR is dependent on the ligands, the androgens. The AR binds as a ligand activated receptor dimer to androgen response elements (AREs), a simple bipartite DNA-binding element, in the promoters of androgen sensitive genes and up-regulates their transcription. This activity is mediated by so called co-activators, such as p160, which establish the link to the basal transcription machinery and to modifiers of the local chromatin structure. Many proteins that interact with the AR with different functional consequences, including co-activation and co-repression, have been described (Gottlieb et al., 1999) (see also: http://ww2.mcgill.ca/androgendb/). Most receptors of the steroid hormone receptor family have two distinct transactivation functions, located respectively in the amino-terminal portion and in the carboxy-terminal portion, that are also involved in ligand binding. These two activation functions act to a certain degree independently of each other. The androgen receptor is an exemption to this rule, inasmuch as the two activation functions appear to be interdependent (Ikonen et al., 1997; Berrevoets et al., 1998; Alen et al., 1999; Bevan et al., 1999; He et al., 1999, He et al., 2000; Hsiao and Chang, 1999).

Section snippets

The androgen receptor CAG repeat

The AR contains a CAG repeat in the first exon within the coding region. This repeat is translated into a poly-glutamine stretch. In 1991 La Spada et al. reported that expansions of the AR CAG repeat to over 40 CAGs determine the X-linked neurodegenerative disease, spinal-bulbar muscular atrophy (SBMA) or Kennedy' disease. This triplet repeat expansion disease (TRED) was the first description of a series of similar neurodegenerative diseases that are caused by CAG repeat expansions (for recent

Functional consequences of the AR CAG repeat length polymorphism in the male reproductive system

Several studies have addressed male infertility but have reported discordant results. Several studies found a correlation of azoospermia or severe oligozoospermia with CAG repeat length (Dowsing et al., 1999; Yoshida et al., 1999; Mifsud et al., 2001; Patrizio et al., 2001). Mifsud et al. calculated that each unit increase in CAG length was associated with a 20% increase in the odds of being azoospermic (Mifsud et al., 2001). Although these data confirm the intuitive correlation between AR

AR CAG repeat length polymorphism and prostate cancer

Androgens are essential for the development and homeostasis of the prostate gland. The growth of most cancers of the prostate depend on androgens and respond to anti-androgen therapy, at least at the beginning of their evolution (for recent reviews see Koivisto et al., 1998; Jenster, 1999; Avila et al., 2001). Escape from anti-androgen sensitivity, observed in later stages of cancer development, evolves through alterations that increase AR activity. These include AR mutations in the hormone

Effects of the AR CAG repeat polymorphism in other tissues

In other tissues, the role of the AR is less clear. In breast epithelium the androgens have been reported to stimulate proliferation but probably only after conversion to estrogens (Tanaka et al., 2000; Schmitt et al., 2001) or by direct binding to the estrogen receptor (Maggiolini et al., 1999). Other studies show anti-proliferative effects of the hormone (Hackenberg and Schulz, 1996). Transfection of the AR into the breast carcinoma cell line MCF-7 leads to androgen induced inhibition of

Somatic alterations of the AR CAG repeat

Since the length of the AR CAG repeat in the germline appears to be related to the risk of cancer in various tissues that express the receptor, somatic reductions of the same repeat in these tissues would be expected to contribute to carcinogenesis. The enhanced androgen dependent mitogenic effect can be inherited or acquired by somatic mutation in analogy to what is observed for other tumor susceptibility genes. This is the more probable since CAG repeats are intrinsically unstable. It is

AR in colon carcinogenesis

The role of sex steroids in colon carcinogenesis is still unclear. Colon polyps are more frequent in men than in women (McCashland et al., 2001). Singh and Langman (Singh et al., 1993) reported an association between breast and colon cancer and, more recently, a reduced risk for colon cancer in postmenopausal women receiving estrogen replacement therapy has been reported (Grodstein et al., 1998). The protective effect of estrogens appears to be mediated by a reduction of tumors with

Conclusions

Extensive data indicate that the AR CAG repeat polymorphism is associated to differential cancer risk in the prostate and in the breast for BRCA1 mutation carriers and somatic alterations of the repeat are apparently related to positive growth selection of neoplastic cells. Taken together these data indicate that the AR, in addition to its prominent role in prostate cancer, may act as a low penetrance cancer susceptibility gene. The intriguing finding is that a given allele can be associated to

Acknowledgements

We thank Adriana Albini and Erika Villa for many helpful discussions and continuous support and Douglas Noonan for critically reading the manuscript.

References (138)

  • T. Ikonen et al.

    Interaction between the amino- and carboxyl-terminal regions of the rat androgen receptor modulates transcriptional activity and is influenced by nuclear receptor coactivators

    J. Biol. Chem.

    (1997)
  • I.A. Klement et al.

    Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice

    Cell

    (1998)
  • M. Li et al.

    Nonneural nuclear inclusions of androgen receptor protein in spinal and bulbar muscular atrophy

    Am. J. Pathol.

    (1998)
  • L.P. Lovely et al.

    Characterization of androgen receptors in a well-differentiated endometrial adenocarcinoma cell line (Ishikawa)

    J. Steroid Biochem. Mol. Biol.

    (2000)
  • T.M. McCashland et al.

    Gender differences in colorectal polyps and tumors

    Am. J. Gastroenterol.

    (2001)
  • A. Mifsud et al.

    Trinucleotide (CAG) repeat polymorphisms in the androgen receptor gene: molecular markers of risk for male infertility

    Fertil. Steril.

    (2001)
  • R.K. Nam et al.

    Significance of the CAG repeat polymorphism of the androgen receptor gene in prostate cancer progression

    J. Urol.

    (2000)
  • M.A. Pereira et al.

    Prevention by chemopreventive agents of azoxymethane-induced foci of aberrant crypts in rat colon

    Cancer Lett.

    (1991)
  • U. Pfeffer et al.

    Alternative splicing of the estrogen receptor primary transcript normally occurs in estrogen receptor positive tissues and cell lines

    J. Steroid Biochem. Mol. Biol.

    (1996)
  • T.R. Rebbeck et al.

    Modification of BRCA1-associated breast cancer risk by the polymorphic androgen-receptor CAG repeat

    Am. J. Hum. Genet.

    (1999)
  • F. Saudou et al.

    Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions

    Cell

    (1998)
  • M. Schmitt et al.

    Dehydroepiandrosterone stimulates proliferation and gene expression in MCF-7 cells after conversion to estradiol

    Mol. Cell. Endocrinol.

    (2001)
  • M.P. Schoenberg et al.

    Microsatellite mutation (CAG24→18) in the androgen receptor gene in human prostate cancer

    Biochem. Biophys. Res. Commun.

    (1994)
  • A.K. Ahman et al.

    Low frequency of microsatellite instability in hereditary prostate cancer

    BJU Int.

    (2001)
  • P. Alen et al.

    The androgen receptor amino-terminal domain plays a key role in p160 coactivator-stimulated gene transcription

    Mol. Cell. Biol.

    (1999)
  • J. Beilin et al.

    Effect of the androgen receptor CAG repeat polymorphism on transcriptional activity: specificity in prostate and non-prostate cell lines

    J. Mol. Endocrinol.

    (2000)
  • C.A. Berrevoets et al.

    Functional interactions of the AF-2 activation domain core region of the human androgen receptor with the amino-terminal domain and with the transcriptional coactivator TIF2 (transcriptional intermediary factor2)

    Mol. Endocrinol.

    (1998)
  • C.L. Bevan et al.

    The AF1 and AF2 domains of the androgen receptor interact with distinct regions of SRC1

    Mol. Cell. Biol.

    (1999)
  • S.N. Birrell et al.

    Role of the androgen receptor in human breast cancer

    J. Mamm. Gland Biol. Neoplasia

    (1998)
  • J.T. Bousema et al.

    Polymorphisms in the vitamin D receptor gene and the androgen receptor gene and the risk of benign prostatic hyperplasia

    Eur. Urol.

    (2000)
  • O. Bratt et al.

    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

    (1999)
  • M.G. Catalano et al.

    Altered expression of androgen-receptor isoforms in human colon-cancer tissues

    Int. J. Cancer

    (2000)
  • G.M. Centola

    Inhibition of endometrial carcinoma cell cultures by a synthetic androgen

    Cancer Res.

    (1985)
  • N.L. Chamberlain et al.

    The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function

    Nucl. Acids Res.

    (1994)
  • C.S. Choong et al.

    Reduced androgen receptor gene expression with first exon CAG repeat expansion

    Mol. Endocrinol.

    (1996)
  • G.A. Coetzee et al.

    Prostate cancer and the androgen receptor

    J. Natl. Cancer Inst.

    (1994)
  • L. Correa-Cerro et al.

    (CAG)nCAA and GGN repeats in the human androgen receptor gene are not associated with prostate cancer in a French–German population

    Eur. J. Hum. Genet.

    (1999)
  • S. Dadze et al.

    The size of the CAG repeat in exon 1 of the androgen receptor gene shows no significant relationship to impaired spermatogenesis in an infertile Caucasoid sample of German origin

    Mol. Hum. Reprod.

    (2000)
  • M.B. Datto et al.

    Targeted disruption of Smad3 reveals an essential role in transforming growth factor beta-mediated signal transduction

    Mol. Cell. Biol.

    (1999)
  • F. de Zegher et al.

    Androgens and fetal growth

    Horm. Res.

    (1998)
  • S.M. Edwards et al.

    Androgen receptor polymorphisms: association with prostate cancer risk, relapse and overall survival

    Int. J. Cancer

    (1999)
  • S. Egawa et al.

    Genomic instability of microsatellite repeats in prostate cancer: relationship to clinicopathological variables

    Cancer Res.

    (1995)
  • S.J. Engle et al.

    Transforming growth factor beta1 suppresses nonmetastatic colon cancer at an early stage of tumorigenesis

    Cancer Res.

    (1999)
  • B.O. Evert et al.

    Cell death in polyglutamine diseases

    Cell Tissue Res.

    (2000)
  • Ferro, P., Dell'Eva, R., Pfeffer, U. 2001. Are there CAG repeat expansion diseases outside the central nervous system?...
  • T. Gao et al.

    Functional activities of the A and B forms of the human androgen receptor in response to androgen receptor agonists and antagonists

    Mol. Endocrinol.

    (1998)
  • E. Giovannucci et al.

    The CAG repeat within the androgen receptor gene and its relationship to prostate cancer

    Proc. Natl. Acad. Sci. USA

    (1997)
  • E. Giovannucci et al.

    CAG repeat within the androgen receptor gene and incidence of surgery for benign prostatic hyperplasia in US physicians

    Prostate

    (1999)
  • B. Gottlieb et al.

    Update of the androgen receptor gene mutations database

    Hum. Mutat.

    (1999)
  • R.P. Grewal et al.

    The mutation properties of spinal and bulbar muscular atrophy disease alleles

    Neurogenetics

    (1998)
  • Cited by (0)

    View full text