Expression of the steroid receptor RNA activator in human breast tumors.
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The expression of the recently described steroid receptor RNA activator (SRA) was measured by semiquantitative reverse transcription-PCR within 27 independent breast tumors, spanning a wide spectrum of grade and estrogen receptor (ER) and progesterone receptor (PR) levels. Subgroup analysis showed that SRA expression was similar in ER+/PR+ (median = 65.5, n = 8) and in ER-/PR- (median = 94.6, n = 5) tumors. Interestingly, SRA expression in these two subgroups was significantly (Mann-Whitney rank-sum test, P < 0.05) lower than that observed in ER+/PR- (median = 156.4, n = 6) and ER-/PR+ (median = 144.8, n = 8) tumors. A variant form of SRA, presenting a deletion of 203 bp within the SRA core sequence, was also observed in breast tumor tissues. The relative expression of this new SRA isoform correlated with tumor grade (Spearman coefficient r = 0.53, n = 27, P = 0.004). These data suggest that changes in the expression of SRA-related molecules occur during breast tumor progression. (+info)
Murine mammary gland carcinogenesis is critically dependent on progesterone receptor function.
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To define the functional relevance of progesterone-initiated intracellular signaling in mammary gland tumorigenesis, the progesterone receptor knockout (PRKO) mouse model was used in the context of an established carcinogen-induced mammary tumorigenesis system. In carcinogen-treated, 7,12-dimethylbenz(a)anthracene (DMBA), pituitary-isografted mice, there was a marked reduction in mammary tumor incidence in PRKO mice as compared with isogenic wild types (WT). Mammary tumors arose in 12 (60%) of 20 WT mice compared with 3 (15%) of 20 PRKO mice by 44 weeks after the initial DMBA treatment. In the absence of a pituitary isograft, mammary tumors developed in 4 (20%) of 20 WT mice versus 4 (20%) of 20 PRKO mice by 47 weeks. At the time of carcinogen administration, the proliferative index of the pituitary-stimulated WT gland was at least 4-fold higher than similarly treated PRKO glands, supporting the importance of PR-mediated proliferative pathways in the genesis of this tumor type. Unlike the WT gland, the PRKO gland was unable to exhibit alveologenesis in response to pituitary isograft stimulation; thus, DMBA-initiated mammary tumors observed in the PRKO were assumed to be exclusively of ductal origin. Compared with previous tested strains, by 47 weeks, a higher incidence of DMBA-induced ovarian tumors was observed in this mouse strain: (a) 4 (20%) of 20 WT mice and 9 (45%) of 20 PRKO mice with a pituitary isograft; and (b) 10 (50%) of 20 WT mice and 10 (50%) of 20 PRKO mice without a pituitary isograft. Despite the host-strain's underlying propensity for DMBA-induced ovarian neoplasms, our studies underscore the specific importance of the PR (as distinct from the estrogen receptor) as a mandatory mediator for those intracellular signaling pathways that are essential for the initiation of the majority of murine mammary tumors induced by DMBA. Apart from providing strong support for progesterone's role in mammary gland tumorigenesis as well as furthering our fundamental understanding of breast cancer etiology, these studies may have implications for the routine use of progestins. (+info)
Overexpression of the Tpl-2/Cot oncogene in human breast cancer.
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Tpl-2/Cot proto-oncogene encodes a serine threonine kinase and was initially cloned as a provirus insertion site in MoMuLV-induced T cell lymphomas in rats. Tpl-2 locus was also shown to be affected by provirus insertion in MMTV-induced mammary carcinomas in mice. The involvement of Tpl-2 in 35 human breast paired tumour specimens versus their corresponding adjacent normal tissue was evaluated. Tpl-2 was found overexpressed in 14 of the 35 breast tumours tested using a semi-quantitative RT - PCR method. Gene amplification was detected in eight out of the 14 specimens overexpressing Tpl-2, suggesting the increased number of copies of Tpl-2 gene as a possible mechanism for Tpl-2 overexpression. Significant association was found between the overexpression of Tpl-2 and stage I of the tumours, indicating that this molecular alteration may be an early event in the development of the disease. Furthermore, overexpression of Tpl-2 was associated with positive progesterone receptor status of the samples. This is the first report on the Tpl-2 oncogene linked to human breast tumours suggesting that it may be a key molecule for the study of human breast cancer. (+info)
Characterization of the progestin receptors in the human TE85 and murine MC3T3-E1 osteoblast-like cell lines.
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Progestins are believed to exert positive effects on bone density through receptors located in osteoblasts. In the present studies, the binding characteristics and regulation of the progestin receptors in two osteoblast-like cell lines were compared with those in human breast lines. Human TE85 and murine MC3T3-E1 osteoblast-like cells contain a single, high-affinity progestin binding site whose affinity and concentration are lower than in human breast cells. The osteoblastic progestin binding sites showed the expected steroid specificity and associated with the cell nuclei when occupied by ligand. The progestin receptors in osteoblastic cells also had sedimentation coefficients similar to those receptors in breast cells. The regulation of the progestin receptor in the osteoblast-like cells was explored by treating them with estradiol. In contrast to the large, rapid change seen in the breast cells, the progestin receptor levels in the MC3T3-E1 cells showed only a small, delayed up-regulation with estradiol treatment. The progestin receptor number in the TE85 cells was unaffected by estradiol. Down-regulation of the progestin receptors was explored by treating the cells with the progestin, norethindrone (NET). NET administration produced a rapid drop in progestin binding sites in the breast cells and a smaller, more gradual decline in MC3T3-E1 progestin binding. While the maximal decrease in receptor number occurred within 24 h in the breast cells, the receptor number was still continuing to fall after 72 h in the MC3T3-E1 cells. The data presented here demonstrate that both human and murine osteoblast-like cells contain a functional progestin receptor whose binding characteristics and regulation are similar, but not identical, to those receptors in other progestin target tissues such as the breast. (+info)
Overexpression of BRCA2 gene in sporadic breast tumours.
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The breast cancer susceptibility gene BRCA2 is expressed in a wide range of tissues as an 11-kb mRNA transcript that encodes a 3418-amino acid protein involved in the response to DNA damage. To obtain better a molecular characterization of BRCA2 expression in sporadic breast cancer, we quantified BRCA2 mRNA by means of RT - PCR in a large series of human primary breast tumours. BRCA2 expression showed wide variations in tumour tissues, being underexpressed in 14/127 (11%) and overexpressed in 25/127 (20%). BRCA2 overexpression (but not underexpression) correlated significantly with Scarff, Bloom and Richardson (SBR) histopathological grade III (P=0.007) and was mainly attributed to nuclear polymorphism (P=0.005) and mitotic index (P=0.048), suggesting that the BRCA2 gene contributes to the proliferation rate in breast tumours. BRCA2 status (under and/or overexpression versus normal expression) was not associated with subsequent relapse and with significantly shorter disease-free survival. The observed disruption of BRCA2 expression is not due to allelic loss, because the latter did not correlate with altered BRCA2 mRNA expression in our tumour series. Taken together, these data suggest the involvement, especially by overexpression, of the BRCA2 gene in sporadic breast tumours, and the existence of another important tumour-suppressor gene in breast cancer, in the 13q12-q13 region. (+info)
Biologic markers as predictors of clinical outcome from systemic therapy for primary operable breast cancer.
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PURPOSE: To determine whether pretreatment clinical features and molecular markers, together with changes in these factors, can predict treatment response and survival in patients with primary operable breast cancer who receive neoadjuvant therapy. PATIENTS AND METHODS: Mitoxantrone, methotrexate (with or without mitomycin), and tamoxifen chemoendocrine therapy was administered to 158 patients before surgery. Clinical response was assessed after four cycles of treatment. Fine-needle aspiration cytology for estrogen receptor (ER), progesterone receptor (PgR), c-erbB-2, p53, bcl-2, Ki67, S-phase fraction (SPF), and ploidy were performed pretreatment and repeated on day 10 or day 21 after the first cycle of treatment. RESULTS: Good clinical response (GCR, defined as complete response or minimal residual disease) was achieved in 31% of patients (49 of 158). Tumor size, nodal disease, response, ER, PgR, c-erbB-2, p53, bcl-2, Ki67, SPF, and ploidy were analyzed as predictors of survival. By univariate analysis, node-positive disease (P =.05), lack of ER (P <.05) and PgR (P <.05), and failure to attain GCR (P =.008) were associated with a significantly increased risk of relapse. A significantly increased risk of death was associated with node-positive disease (P =.02), lack of ER expression (P =.04), and failure to attain GCR. By multivariate analysis, GCR was an independent predictor for survival (P =.05). ER expression (P =.03), absence of c-erbB-2 (P =.03), and a decrease in Ki67 on day 10 or day 21 of the first cycle (P <.05) significantly predicted for subsequent GCR. CONCLUSION: Molecular markers may be used to predict the likelihood of achieving GCR, which seems to be a valid surrogate marker for survival. (+info)
Enhanced prediction of breast cancer prognosis by evaluating expression of p53 and prostate-specific antigen in combination.
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p53 gene mutation is the most common genetic alteration in neoplastic diseases, including breast cancer, for which p53 alteration may indicate poor prognosis. Recent clinical evidence suggests that prostate-specific antigen (PSA) expression may identify breast cancer patients with favourable outcome. Assessment of p53 and PSA in combination, potentially offering improved prediction, has not yet been performed. Extracts from 952 primary breast carcinomas were assayed for PSA and p53 by quantitative enzyme-linked immunosorbent assays (ELISAs) developed by the authors. Concentrations of each marker were classified as negative or positive on the basis of median and 30th percentile cut-off points for p53 and PSA respectively. Patients followed for a median of 6 years having different combinations of negative or positive status for PSA and p53 were compared with respect to the relative risks (RRs) for relapse and death by Cox proportional hazards regression analysis, in which an interaction term was also evaluated, and with respect to disease-free survival (DFS) and overall survival (OS) probabilities by Kaplan-Meier plots and log-rank tests. Multivariate models were adjusted for oestrogen and progesterone receptor status, nodal status, patient age, tumour size, DNA ploidy, S phase fraction and receipt of chemotherapy. Interactions were not found between the status of PSA and p53 in the Cox models, in which PSA-negativity (RR = 1.47, P = 0.020 for DFS, and RR = 1.49, P = 0.023 for OS) and p53-positivity (RR = 1.46, P = 0.017 for DFS, and RR = 1.41, P = 0.033 for OS) were individually associated with prognosis. Evaluation of a combined three-level variable revealed that PSA(-)/p53(+) patients had significantly higher risks for relapse (RR = 2.13, P < 0.001) and death (RR = 2.08, P = 0.001) than PSA(+)/p53(-) patients, and that patients positive or negative for both markers had intermediate risks for the outcome events in the same multivariate analysis (RR = 1.45 for both DFS and OS). The results of our study demonstrate that the assessment of combined PSA and p53 expression status by ELISAs, easily applicable to breast tumour extracts prepared for steroid hormone receptor analyses, may stratify breast cancer patients into groups differing by relapse and death risks of greater magnitude than offered by the assessment of either p53 or PSA alone. (+info)
Detection of loss of heterozygosity at RAD51, RAD52, RAD54 and BRCA1 and BRCA2 loci in breast cancer: pathological correlations.
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Loss of heterozygosity (LOH) in loci of the 15q15.1, 12p13, 1p32, 17q21 and 13q12-13 regions may collaborate in the inactivation of RAD51, RAD52, RAD54, BRCA1, BRCA2 and possibly other genes implicated in the repair of double-stranded DNA and in DNA recombination. We investigate allelic losses in microsatellites of the RAD51, RAD52, RAD54, BRCA1 and BRCA2 regions, and their correlations with nine pathologic parameters in 127 breast carcinomas. The LOH analysis was performed by amplifying DNA by PCR, using 15 markers of the 15q15.1, 12p13.3, 1p32, 17q21 and 13q12-13 regions. LOH was found in the RAD51 region in 32% of tumours, in the RAD52 region in 16%, in RAD54 in 20% and in the BRCA1 and BRCA2 regions in 49% and 44% respectively. Significant correlations between one or more regions with concomitant LOH and pathologic parameters were observed with respect to age (P = 0.008), oestrogen receptor content (P = 0.03), progesterone receptors (P = 0.003), higher grade (P = 0.001), more advanced stage (P = 0.004) and peritumoural vessel involvement (P < 0.0001). The number of cases in which LOH was observed simultaneously in two or more regions was always higher than expected on the basis of their statistical probability, and curiously, the three patients with LOH at five regions concomitantly were under the age of 30 years. These results suggest that LOH at these regions could be related to breast cancer, and probably to a poor tumour prognosis. (+info)