Inhibitory effect of estrogens on GCDFP-15 mRNA levels and secretion in ZR-75-1 human breast cancer cells.
In order to better understand the mechanisms responsible for the antagonism between steroids in human breast cancer cells, we have studied the effect of 17 beta-estradiol (E2), dihydrotestosterone (DHT), and dexamethasone (DEX) alone or in combination on the expression of the breast gross cystic disease fluid protein-15 (GCDFP-15) in ZR-75-1 cells. Incubation with E2 markedly decreased basal GCDFP-15 mRNA levels accompanied by a parallel inhibition of the secretion of this tumor marker, the estrogenic effect being exerted at a half-maximal concentration of about 44 pM E2. The inhibitory effect of E2 on GCDFP-15 expression was competitively reversed by the antiestrogen LY156758. In addition, 1 nM E2 inhibited the marked stimulation induced by 1 nM DHT or 300 nM DEX on GCDFP-15 mRNA accumulation and on the secretion of the glycoprotein. However, at the concentration used, E2 reversed by only 65% the stimulation achieved by the combination of DHT and DEX on GCDFP-15 mRNA levels. It is of interest to mention that the effect of DHT, DEX, and E2 on GCDFP-15 expression is opposite to the respective effect of each steroid on ZR-75-1 cell proliferation. The present data on the regulation of GCDFP-15 mRNA demonstrate an estrogen-induced inhibition of mRNA levels under physiological conditions, thus offering a unique opportunity to study the mechanisms involved in the down-regulation of gene expression by estrogens and to achieve a better understanding of the antagonism between estrogens, androgens, glucocorticoids, and progestins in breast cancer cells. Furthermore, GCDFP-15 could well be a good marker for monitoring the response to androgens and antiestrogens during the course of breast cancer therapy.
Simard
J
J
Medical Research Council Group in Molecular Endocrinology, Laval University Medical Center, Quebec, Canada.
Hatton
A C
AC
Labrie
C
C
Dauvois
S
S
Zhao
H F
HF
Haagensen
D E
DE
Labrie
F
F
D001053:Apolipoproteins; D053399:Apolipoproteins D; D015152:Blotting, Northern; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D002352:Carrier Proteins; D002455:Cell Division / Q000187:drug effects; D015342:DNA Probes; D003907:Dexamethasone / Q000494:pharmacology; D013196:Dihydrotestosterone / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006023:Glycoproteins; D006801:Humans; D026901:Membrane Transport Proteins; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics*; D020849:Raloxifene Hydrochloride
C024328:APOD protein, human; D001053:Apolipoproteins; D053399:Apolipoproteins D; D002352:Carrier Proteins; D015342:DNA Probes; D004965:Estrogen Antagonists; D004967:Estrogens; D006023:Glycoproteins; D026901:Membrane Transport Proteins; D009363:Neoplasm Proteins; C488892:PIP protein, human; D010880:Piperidines; D012333:RNA, Messenger; D013196:Dihydrotestosterone; D020849:Raloxifene Hydrochloride; D004958:Estradiol; D003907:Dexamethasone