Medroxyprogesterone acetate (MPA), a compound frequently used in the treatment of breast cancer in women, exerts its main inhibitory action through an androgen receptor-mediated action, whereas its glucocorticoid-like activity could play an additional role at high concentrations.
We screened thirteen male breast cancers for the presence of germline mutations in exons 2 and 3 encoding the DNA-binding domain of the androgen receptor.
In summary, MDA-MB-453 cells express high levels of functional AR, and thus provide a valuable in vitro model for further studies on androgen regulation of gene expression, and perhaps cell proliferation in breast cancer.
Our group have identified 16 androgen receptor gene alterations in patients with androgen insensitivity syndrome, an amino acid substitution in a patient with a partial androgen insensitivity syndrome and a breast cancer.
For example, metabolites of DHT with oestrogenic activity, or androgen binding to receptors other than the AR, may explain the divergent responses to androgens observed in different breast cancer cell lines.
In more recent years, however, mutations in the AR gene have been described in a number of diverse clinical conditions, from male infertility to prostate and breast cancer through to a form of motor neurone disease (Kennedy's disease).
The TP53 gene is involved in breast cancer development in the Li-Fraumeni syndrome and Li-Fraumeni syndrom-like families, whereas germ-line mutations in the androgen receptor (AR) gene is present in a subset of male breast cancers.
Certain germline mutations (607Arg-Gln, 608Arg-Lys) in the androgen receptor gene have been associated with the occurrence of breast cancer in males suffering from partial androgen insensitivity.
Two heritable gene defects have been associated with a predisposition to male breast cancer development, ie., germ-line mutations in the breast cancer susceptibility gene BRCA2 and the androgen receptor (AR) gene.
The present data indicate that androgens can down-regulate bcl-2 protooncogene levels via an androgen receptor-mediated mechanism, thus providing a novel mechanism for their known inhibitory effect on breast cancer cell growth.
These findings indicate that MPA is an AR agonist and suggest that the in vivo effects of MPA in breast cancer patients may in part be mediated by the AR.
We found no evidence for an association between AR exon 1 CAGn length and breast cancer risk in women under the age of 40, despite having 80% power to detect modest effects.
Although AR is expressed in breast cancer and the impact of androgen and AR on breast cancer has been recognized, the role of the CAG repeats in breast cancer remains unknown.
The present findings showing frequent expression of structurally unaltered androgen receptor in an advanced stage of EMPD may provide a rational basis for hormone therapy, which is widely used in the treatment of metastatic prostate cancer and androgen receptor-positive breast cancer recurrence.
Although CAIS is the best known phenotype, recent studies from our laboratory and elsewhere show that malfunction of the AR is associated with many androgen-regulated diseases or conditions that cross traditional clinical disciplines ranging from paediatrics (ambiguous genitalia), gynaecology (primary amenorrhoea), urology (prostate cancer), neurology (spinal bulbar muscular atrophy), reproductive medicine (male infertility), orthopedics (rheumatoid arthritis), oncology (breast cancer) and dermatology (hirsutism, baldness and acne).