The pro‐cathepsin D of Mr 52,000 is regulated by estrogens via the estrogen receptor (RE) and is secreted by breast cancer cells in vitro. In an attempt to predict the hormone responsiveness of ...breast cancer in vivo, we have assayed total 52K cathepsin D and its precursor in the primary breast cancer cytosol of 36 patients treated before surgery with 30 mg of tamoxifen daily for 1 to 5 weeks (average, 3 weeks). Compared to a similar control population, total 52K cathepsin D was increased by tamoxifen (P = 0.02) but less so than its precursor (P < 0.001). Furthermore, 45% of the RE‐positive tumors from tamoxifen‐treated patients had a higher cathepsin D precursor concentration than the same type of tumor from control patients, or than RE‐negative tumors from tamoxifen‐treated patients. This 3‐week challenge test was probably too short to avoid partial estrogenic activity of tamoxifen (flare) and the authors infer that longer time of treatment would decrease rather than increase the concentration of cathepsin D in the RE‐responsive tumors. However, two cancers from patients with relapses after prolonged tamoxifen treatment (>6 months) also had high concentrations of 52K cathepsin D and its precursor. The authors conclude that the concentration of cathepsin D and its precursor in breast cancer cytosol can be increased by short‐term tamoxifen treatment, suggesting that these tumors are estrogen responsive.
Using an immunoenzymatic assay, cathepsin-D concentrations were measured in the cytosol of human endometrium biopsies. The level of cathepsin-D was higher in the luteal phase than in the follicular ...phase (P less than 0.01), suggesting increased accumulation by progesterone. Induction by progestin was confirmed by immunoprecipitation of cathepsin-D from a lysate of epithelial endometrial cells previously treated in primary culture with R5020 (10 nM); estradiol (10 nM) had no effect. Immunohistochemistry showed that cathepsin-D is mainly localized in the epithelium and that its level is higher in the luteal phase. The plasma level of cathepsin-D was stable during the menstrual cycle, ranging between 2.5-10 pmol/mL, but increased slightly during pregnancy. The mean level of cathepsin-D was higher in 19 endometrial carcinoma than in 20 normal endometrium, but was not correlated with steroid receptor status. However, using 15 pmol/mg protein as a cut-off level, the cathepsin-D status (high or low) was correlated with the degree of myometrial invasion (greater than or equal to one third) by adenocarcinoma cells, whereas steroid receptor status was not. We conclude that cathepsin-D is induced by progesterone in human endometrium, as it is in normal rat uterus, and we suggest that a low concentration of cathepsin-D in the cytosol of endometrial adenocarcinoma may indicate a favorable prognosis, since it is correlated with low myometrial invasion.
Most hereditary nonpolyposis colorectal cancer (HNPCC) cases are caused by germline mutations of mismatch repair (MMR) genes (i.e.,
MLH1,
MSH2, or
MSH6). Here we describe six novel mutations in ...patients referred for genetic assessment. All of these mutations lead to premature translation termination. Five single base pair deletions lead to frameshift (
MLH1: g.38-39insCCCA, g.1971del.T;
MSH2: g.163del.C, g.746del.A;
MSH6: g.3320del.A) and one nonsense mutation in
MSH2 g.1030C>T leads to a stop codon: p.Q344X. In one patient, the previously described
MLH1 nonsense mutation g.806C>G was found in a homozygous state. In this patient, the familial histories of both the mother and father suggested HNPCC syndrome. This patient developed colon cancer at 22 years of age, suggesting a more aggressive phenotype. The results of our study provide further insight into the mutational spectrum of MMR genes in HNPCC families.
The c-myc, c-erbB-2, hst and int-2 oncogenes are frequently amplified and/or overexpressed in human breast carcinomas. We studied the effect of tamoxifen on RNA levels of these oncogenes in 19 breast ...cancer patients treated for 3 weeks prior to surgery as compared with 22 control patients. RNA levels were measured by in situ hybridization coupled with computer-aided quantification. c-myc and c-erbB-2 expression was high in the control population (mean values: 23.4 and 29.1 grains/cell respectively) and significantly decreased in the tamoxifen-treated population (mean values: 14.6 and 7.4 grains/cell respectively) (P = 0.018, P = 0.003 respectively); hst and int-2 RNA levels were low (2-6 grains/cell) and not significantly altered by the treatment. There was a correlation between gene amplification and expression for c-erbB-2 (P = 0.0005) and hst (P = 0.02) in the control population. Elevated c-erbB-2 RNA level was correlated with the absence of estrogen (P = 0.02) or progesterone (P = 0.05) receptors. In the ER+ population, the tamoxifen-treated group had significantly lower c-myc expression levels than the control group (P = 0.04) which is in agreement with the estrogen induction of c-myc in ER+ T47D cell line and its inhibition by antiestrogens. Surprisingly, c-erbB-2 expression in the tamoxifen-treated group was significantly diminished in the ER- (P = 0.02) and PR- (P = 0.01) populations. This effect was not observed in the ER- BT474 cell line. These results suggest that in vivo tamoxifen decreases c-myc and c-erbB-2 RNA levels in breast cancer cells via two different mechanisms. To our knowledge this is the first evidence of in vivo down regulation of a gene by tamoxifen in ER- breast cancer cells.
Many hormones exert their effects through specific nuclear receptors which belong to a superfamily of ligand-activated transcription factors. These receptors control target gene expression through ...the recruitment of different cofactors acting as transcription activation or repression mediators, generally as parts of multiprotein complexes. The importance and the role in physiopathology of these different cofactors only begin to be defined. Different types of alterations affecting genes coding nuclear receptor transcription cofactors have indeed been described in cancer. The most important examples are gene amplification that leads to overexpression and gene mutations or translocations introducing qualitative modifications. This paper aims at bringing together the corresponding literature and focuses on gene alterations observed in solid tumors.
The interaction of suriclone and two of its main metabolites with central type benzodiazepine receptors, which had been labeled in vivo with the radioligand 11CRO 15-1788, was investigated in living ...baboons. The concentration of radioligand bound to the receptors, as measured in brain transverse sections by positron emission tomography, decreased rapidly after the i.v. administration of suriclone at doses known to induce pharmacological effects. The rate and extent to which 11CRO 15-1788 binding was displaced increased with increasing doses of suriclone. The half-inhibitory dose (ID50) was determined to be 0.08 mg/kg in vivo. The rapid inhibitory effect of suriclone on the in vivo binding of 11CRO 15-1788 in the brain seems to reflect its ability to act at the GABA-benzodiazepine receptor complex, at or near to the benzodiazepine binding site, to induce its pharmacological activity. The i.v. injection of the demethylated metabolite of suriclone, RP 35,489, only caused a slight displacement of 11CRO 15-1788 binding even at a dose of 2 mg/kg. Thus, suriclone appears to be more potent than RP 35,489 to displace the benzodiazepine 11C antagonist in vivo. The sulfoxide metabolite, RP 46,166, did not significantly change the kinetics of 11CRO 15-1788 binding in the brain. The slight effects produced by high doses of RP 35,489 and RP 46,166 on 11CRO 15-1788 binding in the brain suggest that these metabolites are probably not responsible for the expression of biological activity of suriclone mediated by benzodiazepine receptors.
PDF
