The androgen receptor CAG repeat: a modifier of 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)
- et al.
The androgen receptor (AR) in syndromes of androgen insensitivity and in prostate cancer
J. Steroid Biochem. Mol. Biol.
(2001) - et al.
Analysis of the CAG repeat region of the androgen receptor gene in a kindred with X-linked spinal and bulbar muscular atrophy
J. Neurol. Sci.
(1992) - et al.
Linkage between male infertility and trinucleotide repeat expansion in the androgen-receptor gene
Lancet
(1999) - et al.
Somatic alterations of the androgen receptor CAG repeat in human colon delineate a novel mutation pathway
Cancer Genet. Cytogenet.
(2000) - et al.
The CAG repeat within the androgen receptor gene and benign prostatic hyperplasia
Urology
(1999) - et al.
The androgen receptor exon 1 trinucleotide repeat does not act as a modifier of the age of presentation in breast cancer
Eur. J. Cancer
(2000) - et al.
Androgen receptor mediated growth control of breast cancer and endometrial cancer modulated by antiandrogen- and androgen-like steroids
J. Steroid Biochem. Mol. Biol.
(1996) - et al.
Activation function 2 in the human androgen receptor ligand binding domain mediates interdomain communication with the NH(2)-terminal domain, J. Biol. Chem. 274, 37219-37225.
J. Biol. Chem.
(1999) - et al.
FXXLF and WXXLF sequences mediate the NH2-terminal interaction with the ligand binding domain of the androgen receptor
J. Biol. Chem.
(2000) - et al.
Isolation and characterization of ARA160 as the first androgen receptor N-terminal-associated coactivator in human prostate cells
J. Biol. Chem.
(1999)