Identification of apolipoprotein D as a cardioprotective gene using a mouse model of lethal atherosclerotic coronary artery disease.

Mice with homozygous null mutations in the HDL receptor (scavenger receptor class B, type I, or SR-BI) and apolipoprotein E (apoE) genes [SR-BI/apoE double KO (SR-BI(-/-)/apoE(-/-) or dKO) mice] spontaneously develop occlusive, atherosclerotic coronary artery disease (CAD) and die prematurely (50% mortality at 42 d of age). Using microarray mRNA expression profiling, we identified genes whose expression in the hearts of dKO mice changed substantially during disease progression [at 21 d of age (no CAD), 31 d of age (small myocardial infarctions), and 43 d of age (extensive myocardial infarctions) vs. CAD-free SR-BI(+/-)/apoE(-/-) controls].

Immunolocalization of apolipoprotein D, androgen receptor and prostate specific antigen in early stage prostate cancers.

Purpose: To determine the cellular distribution and levels of immunohistochemical staining for apolipoprotein D (Apo-D), prostate specific antigen (PSA) and androgen receptor (AR) in early stage prostate cancers.

Materials And Methods: Cellular distribution of Apo-D, PSA and AR in 30 stage A/B prostate cancers and in non-malignant glandular tissue contained in the same sections was detected immunohistochemically, and staining was evaluated by computerized video image analysis.

Results: Staining for Apo-D (percentage positive cellular area) was significantly increased in tumor cells of early stage prostate cancers compared with non-malignant glandular tissue.

Interleukin-4 and interleukin-13 inhibit estrogen-induced breast cancer cell proliferation and stimulate GCDFP-15 expression in human breast cancer cells.

Human breast carcinomas are frequently infiltrated by inflammatory cells secreting several cytokines which may regulate the activity of both immune cells and neoplastic cells. The present study was designed to examine the potential action of interleukin-4 (IL-4) and interleukin-13 (IL-13) in human breast cancer cells. Exposure of ZR-75-1 breast cancer cells to IL-4 or IL-13 for 10 days decreased the amplitude of the mitogenic action of 17 beta-estradiol by 75% and 55%, respectively, while these cytokines failed to change basal cell proliferation.

Interleukin-6 inhibits the potent stimulatory action of androgens, glucocorticoids and interleukin-1 alpha on apolipoprotein D and GCDFP-15 expression in human breast cancer cells.

Our study was designed to investigate the potential interaction between steroid hormones and interleukin-6 (IL-6) in the regulation of apolipoprotein D (apo-D) and gross cystic disease fluid protein 15 (GCDFP-15) expression in ZR-75-1 human breast cancer cells. We first observed that exposure to IL-6 for 6-14 days decreased basal apo-D and GCDFP-15 secretion by 50% and 23%, respectively. In the same experiment, such treatment with IL-6 decreased cell proliferation by approximately 40% after 6 and 14 days of incubation.

Differential expression of apolipoprotein-D and prostate specific antigen in benign and malignant prostate tissues.

Purpose: To investigate Apolipoprotein-D (Apo-D) and prostate specific antigen (PSA) immunohistochemical staining of nonmalignant and malignant human prostate tissues.

Materials And Methods: Apolipoprotein-D and PSA immunoreactivity were evaluated by video image analysis in nonmalignant prostates and in 30 stage D2 prostate cancers.

Results: Apolipoprotein-D was detected in all 30 tumors, and the level of staining was elevated in comparison to age-matched nonmalignant prostates (p < 0.

Mitogenic effect of the 15-kDa gross cystic disease fluid protein (GCDFP-15) on breast-cancer cell lines and on immortal mammary cells.

The biological significance of a major protein component in the fluid of gross cystic breast disease and a recognized marker of apocrine metaplasia, i.e. the 15-kDa glycoprotein (GCDFP-15), is presently unknown.

Potent stimulatory effect of interleukin-1 alpha on apolipoprotein D and gross cystic disease fluid protein-15 expression in human breast-cancer cells.

To better understand the multiple hormonal control of the expression of apolipoprotein D (apo-D) and gross cystic disease fluid protein-15 (GCDFP-15, also designated prolactin-inducible protein), which are 2 major proteins found in benign breast-disease fluid, we investigated their regulation by interleukin-1 alpha (IL-1 alpha) in the presence or absence of steroid hormones in ZR-75-1 human breast cancer cells. Exposure of these cells to IL-1 alpha decreased basal cell proliferation by half and markedly reduced the mitogenic action of 17 beta-estradiol (E2), the half-maximal inhibitory effect being exerted at 1.5 pM.

Inverse relationships between cell proliferation and basal or androgen-stimulated apolipoprotein D secretion in LNCaP human prostate cancer cells.

We have recently demonstrated that the biphasic action of androgens on LNCaP cell proliferation is opposite to their effect on apolipoprotein D (apo-D) secretion, the stimulation of apo-D secretion being associated with a steroid-induced inhibition of cell proliferation. To further characterize the control of apo-D expression in LNCaP cells, we studied basal as well as androgen-induced apo-D secretion in slowly proliferating, low-passage (LP; 20-29th) and rapidly proliferating high-passage (HP; 111-117th) cell cultures. For comparison, the androgen-induced stimulation of prostate specific antigen secretion was also investigated in LP and HP cell cultures.

Additive stimulatory action of glucocorticoids and androgens on basal and estrogen-repressed apolipoprotein-D messenger ribonucleic acid levels and secretion in human breast cancer cells.

Recent elucidation of the amino acid sequence of the progesterone-binding protein GCDFP-24, the major protein found in human breast gross cystic disease fluid, reveals that this glycoprotein corresponds to apolipoprotein-D (apo-D), a member of the alpha 2-microglobulin superfamily which binds small hydrophobic ligands. The present study describes the multiple hormonal control of apo-D mRNA levels, intracellular protein content, as well as secretion compared to cell proliferation in human ZR-75-1 breast cancer cells. In these cells, exposure to the synthetic glucocorticoid dexamethasone (DEX) markedly decreases basal as well as 17 beta-estradiol (E2)-induced cell proliferation while causing a maximal 10-fold stimulation of apo-D secretion in the presence or absence of E2.

Secretion of breast gross cystic disease fluid proteins by T47D breast cancer cells in culture--modulation by steroid hormones.

The effect of steroid hormones on modulating the secretion rates of three human breast gross cystic disease fluid proteins (GCDFP-15, GCDFP-24, and GCDFP-44) by T47D breast carcinoma cells in tissue culture was evaluated. Androgens (dihydrotestosterone or fluoxymesterone) were capable of stimulating the secretion rates for all three GCDFP's while showing a minimal trend toward slowing the growth rate of T47D cells. This is the first study which shows that androgens can specifically stimulate all three of the major breast GCDFP's concomitantly.

Stimulatory effect of oestradiol-17 beta and tamoxifen on gross cystic disease fluid protein 15,000 production and mRNA levels in T47D human breast cancer cells.

Oestradiol-17 beta and tamoxifen regulate the synthesis of a gross cystic disease fluid protein (GCDFP-15) in T47D human breast cancer cells. Dose-response curves of GCDFP-15 mRNA contents and GCDFP-15 levels in culture media and cells versus hormone or antihormone concentration have been established. Production of GCDFP-15 was increased by oestradiol-17 beta, tamoxifen and 4-OH tamoxifen.

Stimulation of apolipoprotein D secretion by steroids coincides with inhibition of cell proliferation in human LNCaP prostate cancer cells.

Although steroid hormones are known to play a predominant role in the regulation of cell growth in hormone-sensitive cancers, their mechanisms of action, especially their interaction with growth factors and/or growth inhibitors, is poorly understood. We have recently observed that the effects of androgens and estrogens on the expression of the major protein found in human breast gross cystic disease fluid, protein-24, are opposite to their respective action on cell proliferation in human breast cancer cell lines. Somewhat surprisingly, the recent elucidation of the amino acid sequence of this progesterone binding protein reveals that this tumor marker is apolipoprotein D (apo D), a member of a superfamily of lipophilic ligand carrier proteins.

Is cystic disease related to breast cancer?

Human breast cystic disease is a common premenopausal benign breast condition. Apocrine metaplasia of normal breast epithelium is the lesion that allows cysts to develop. Apocrine metaplasia and breast cysts occur frequently in association with other proliferative changes in breast epithelium, especially breast epithelial hyperplasia.

Opposite effects of estrogen and the progestin R5020 on cell proliferation and GCDFP-15 expression in ZR-75-1 human breast cancer cells.

We have recently demonstrated that physiological concentrations of androgens caused a marked inhibition of basal and 17 beta-estradiol (E2)-induced cell growth in ZR-75-1 human breast cancer cells. Moreover, these steroids exert effects on GCDFP-15 (gross cystic disease fluid protein-15) expression that are opposite to their above-indicated actions on cell proliferation. The synthetic progestin R5020 (17.

Immunologic and steroid binding properties of the GCDFP-24 protein isolated from human breast gross cystic disease fluid.

A major protein of human breast cyst fluid, termed GCDFP-24, has the property of specifically binding progestins. The purified glycoprotein, of 24,000 apparent molecular weight, bound pregnenolone and progesterone with highest affinity. The association constant for binding of progesterone was 1 X 10(6)L/mol by Scatchard analysis, and there was one binding site per molecule.

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.

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.

Renal dysfunction associated with ciprofloxacin.

We cared for a 64-year-old woman who experienced increased serum creatinine levels after 8 days of ciprofloxacin therapy. She had previously received a course of several antibiotics, including gentamicin. Renal function returned to normal 18 days after the ciprofloxacin was discontinued.

Expression of GCDFP-15 in breast carcinomas. Relationship to pathologic and clinical factors.

A retrospective immunoperoxidase staining study for a glycoprotein isolated from human breast gross cystic disease fluid (GCDFP-15) in 562 primary breast carcinomas in 539 patients was conducted to correlate its immunohistochemistry with pathologic and clinical factors. Overall, 55% of the carcinomas studied stained positively for GCDFP-15. In certain histologic subtypes, the percentage of carcinomas that stained positively was greater: those subtypes with apocrine histologic features (75%), intraductal carcinoma (70%), and infiltrating lobular carcinoma with signet-ring cell differentiation (90%).

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.

Hepatic clearance and metabolism in the rat of a human breast cancer associated glycoprotein (GCDFP-15).

Gross Cystic Disease Fluid Protein (GCDFP-15) is a 60,000 dalton glycoprotein isolated from human breast cyst fluid, composed of four 15,000 dalton monomers. Carbohydrate analysis indicates that each monomer has a single carbohydrate chain of the complex type. GCDFP-15 intravenously injected into rats showed a rapid circulatory clearance, the rate of clearance being faster in female animals [t1/2 = 12.

Immunoperoxidase localization of GCDFP-15 with mouse monoclonal antibodies versus rabbit antiserum.

Five monoclonal antibodies (Mabs) raised against separate determinants on a breast gross cystic disease fluid protein of 15 KD (GCDFP-15) were compared to one another and to a rabbit antiserum (Rb) against GCDFP-15 by radioimmunoassay (RIA) and by immunoperoxidase localization in paraffin-embedded tissues. All five Mabs and the Rb were equivalent in recognition of GCDFP-15 in solution, as determined by RIA. However, two of the Mabs (A5, B15) showed only minimal binding to GCDFP-15 in paraffin-embedded tissues, whereas the other three Mabs (B1, B4, D6) were equivalent to the Rb in staining intensity.

Breast gross cystic disease protein 15 in human breast cancer in culture.

Media from explants of 120 human breast cancers cultured for 24 h were analysed for breast gross cystic disease protein 15 (GCDFP-15). The protein was detected in media from 94 tumours (73%) in concentrations varying from 1.5 to 2100 ng/ml.