Steroid hormone regulation of prostate-specific antigen gene expression in breast cancer

Abstract

Summary We have recently reported that about 30-40% of female breast tumours produce prostate-specific antigen (PSA) and that PSA production is associated with the presence of oestrogen (ER) and progesterone (PR) receptors. We have now developed a tissue culture system to study the regulation of the PSA gene in breast cancer. The breast carcinoma cell line T-47D produces PSA when stimulated by androgens, progestins and glucocorticoids/mineralocorticoids but not oestrogens. PSA mRNA appears approximately 2 h after stimulation; PSA protein appears after 4-8 h. Among 38 compounds tested, only androgens and progestins were able to stimulate PSA production at concentrations below 10-9 M. Evidence that the progesterone and androgen receptors can regulate the PSA gene independently was provided as follows: (a) the progestin norgestimate, which does not bind to the androgen receptor, up-regulates the PSA gene at concentrations as low as 10-10 M; (b) triamicinolone acetonide, which does not bind to the androgen receptor (AR) but binds to the PR, acts similarly to norgestimate; (c) the antiandrogen cyproterone acetate, which blocks the androgen receptor but has progestational activity, up-regulates the PSA gene at concentrations as low as 10-10 M; (d) the antiprogestin mifepristone completely blocks the stimulation of the specific progestin norgestimate. Our tissue culture system identified androgen -progestin agonist activities of 17a-ethinyloestradiol, the antioestrogen RU56, 187 and the antiprogestin mifepristone. Our data suggest that the expression of the PSA gene in the female breast is under the control of androgens and progestins. Our tissue culture system is a highly sensitive in vitro method for evaluating the biological activity of candidate compounds having agonist and antagonist steroid hormone activity.

Serum total PSA and free PSA in breast tumors

“…This could be attributed to disrupted hormonal balance in such cases leading to aberrant expression of hormone dependent genes like PSA which is normally under hormonal control and upregulated by androgens and progesterone [5,27,28]. Many other authors have, however, failed to depict any such rise in PSA level in breast tumor cases [9,10].…”

“…PSA, found in a very low but detectable levels in the circulation of women, is likely to be originated from breast tissue [4]. Similar to prostate PSA, production of breast PSA is said to be under hormonal control and androgens in particular are believed to upregulate the expression of PSA gene through androgen receptor [5,6].…”

Prostate-specific antigen and gross cystic disease fluid protein-15 are co-expressed in androgen receptor-positive breast tumours

“…but not by oestradiol. in T-47D human breast cancer cells (Zarghami et al 1997). The primary substrates for PSA are semenogelin and fibronectin.…”

“…Androgens regulate the synthesis and secretion of both PSA (Zarghami et al 1997) and GCDFP-15 (Myal et al 1991) in T47D human breast cancer cells. Therefore.…”

Breast and prostate cancer

“…PSA is also secreted by extra-prostatic sources. It is also interesting observation that 30-40% of female breast tumours produce PSA which is associated with the positive oestrogen receptor (ER) status (15). In addition to this, like human glandular kallikrein (hK2), the breast carcinoma cell-line like T-47D produces PSA when stimulated by glucocorticoids/mineralocorticoids and other steroid hormones (16).…”