Regulation of Progesterone-Binding Breast Cyst Protein GCDFP-24 Secretion by Estrogens and Androgens in Human Breast Cancer Cells: A New Marker of Steroid Action in Breast Cancer*

Abstract

We have previously demonstrated that androgens are potent inhibitors of breast cancer cell proliferation under both basal and estrogen-induced incubation conditions, while they suppress expression of the estrogen and progesterone receptors. To better understand the mechanisms responsible for the antagonism between androgens and estrogens in breast cancer and to obtain a new tumor marker for the actions of these two steroids, we have investigated the effects of androgens and estrogens on expression of the major protein found in human breast gross cystic disease fluid, namely GCDFP-24. This study was performed in ZR-75-1 and MCF-7 human breast cancer cells. After a 9-day incubation period, physiological concentrations of 17 beta-estradiol stimulated proliferation of ZR-75-1 and MCF-7 cells by 2- to 3.5-fold while simultaneously exerting a marked 70-90% inhibition of GCDFP-24 secretion. The estrogenic effects on GCDFP-24 secretion and cell proliferation were both competitively blocked by simultaneous incubation with the new steroidal pure antiestrogen EM-139. On the other hand, a maximal concentration (10 nM) of the nonaromatizable androgen dihydrotestosterone decreased by 50% the proliferation of ZR-75-1 cells; the half-maximal inhibitory effect was exerted at 0.01 nM. The androgen exerted a 3- to 4-fold stimulatory effect on GCDFP-24 secretion at an EC50 value of 0.01 nM. The effect of dihydrotestosterone on these parameters was competitively blocked by simultaneous incubation with the pure antiandrogen OH-flutamide. The present data show that the effects of estrogens and androgens in ZR-75-1 cells on GCDFP-24 secretion and cell growth are opposite. Similarly, in MCF-7 cells, estrogens stimulate cell growth, while GCDFP-24 secretion is inhibited. The present data also suggest that GCDFP-24 could well be a good biochemical marker for monitoring the response to androgenic and antiestrogenic compounds in the therapy of advanced breast cancer.

A strong association between body fat mass and protein profiles in nipple aspirate fluid of healthy premenopausal non-lactating women

“…Because testosterone and progesterone were shown to up-regulate and estradiol to downregulate ZAG, apoD and GCDFP-15 in breast cancer cell cultures [11][12][13][14][15][16], we hypothesized that levels of these hormones might be significant predictors for NAF protein profiles. However, no differences in levels of testosterone and progesterone were detected, and only estradiol was marginally higher in type I compared to type II secretors (P=0.08) in univariate analyses.…”

“…The expression of type I NAF proteins has been studied in cultures of malignant mammary epithelial cells. In these cultures, androgens (dihydrotestosterone or fluoxymesterone) stimulated the secretion of ZAG, apoD and GCDFP-15 into the culture media [11][12][13][14], progesterone and prolactin up-regulated GCDFP-15 expression [15,16], and estradiol decreased the synthesis of GCDFP-15 and apoD [12][13][14]. In contrast, Zhou et al showed that testosterone, progesterone, and tamoxifen decreased apoD mRNA expression in the mammary glands of ovariectomized rhesus monkeys [17].…”

TReP-132 Controls Cell Proliferation by Regulating the Expression of the Cyclin-Dependent Kinase Inhibitors p21WAF1/Cip1 and p27Kip1

“…The cellular DNA content was determined with fluorochrome 3,5-diaminobenzoic acid free acid (DABA) as described previously (21,74). To analyze growth curves of HTO cell clones, cells were plated in 24-well plates at an initial density of 3 ϫ 10 3 cells per well and 24 h later were grown in the presence or absence of Dox (2 g/ml).…”

Retinoic Acid-induced Expression of Apolipoprotein D and Concomitant Growth Arrest in Human Breast Cancer Cells Are Mediated through a Retinoic Acid Receptor RARα-dependent Signaling Pathway

“…The mechanisms responsible for this marked induction of apoD mRNA by retinoids are presently unknown. However, it seems likely that their elucidation could contribute to clarify the role of these compounds in the biochemical path-ways leading to apoD-increased expression in specific conditions, such as growth arrest and cell differentiation of breast cancer cells, as well as in peripheral nerve regeneration processes (11,12,21,22).…”