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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study, we analyzed 105 paired sporadic primary breast tumor and normal tissue samples for loss of heterozygosity (LOH) on chromosome 17, using 12 polymorphic markers. We have identified partial or interstitial LOH in five separate regions of chromosome 17. Two of the deleted regions lie on the short arm of the chromosome, the first (region I, D17S5) in the telomeric part, distal to TP53 and the second spanning the TP53 gene (region II). Three of the five deleted regions lie on the long arm of chromosome 17: region III, on the proximal long arm between D17S250 and THRA1; region IV, between D17S776 and D17S579, including the BRCA1 gene, and region V, located distal to D17S733. No statistically significant correlations were observed between clinicopathological characteristics or steroid hormone receptor status and deletion of either region I or II. However, patients whose tumors had LOH for region I showed relapse or death more frequently than patients with tumors informative for this region but without LOH (p = 0.002). Statistically significant correlations between LOH at each of the three deleted regions of 17q and a high mitotic index were observed (region III, p = 0.005; region IV, p = 0.02, and region V, p = 0.004). In addition, LOH at region IV showed a significant association with paucity of estrogen receptors (p = 0.01). Our results show a complex pattern of LOH on chromosome 17 in breast cancer and a correlation of these events with different clinical parameters. This pattern suggests that particular subsets of allele loss may contribute specifically to different clinically defined subsets of sporadic breast tumors.
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PMID:Five distinct deleted regions on chromosome 17 defining different subsets of human primary breast tumors. 747 29

Oncogenesis is a process resulting from genetic events which cause loss of growth control or inhibition of appropriate cell death. The Bcl-XL protein is a recently discovered member of the bcl-2 family which has been shown to protect cells from some forms of programmed cell death, but has not yet been implicated in the genesis of human carcinomas. In this report we explore the role of Bcl-XL overexpression in protecting cancer cells from p53-mediated apoptosis. Increased levels of Bcl-XL were found in a subset of primary human breast carcinomas, as well as in the breast cancer line, T47D. T47D cells were then transfected with a temperature-sensitive mutant of the tumor suppressor p53 (p53ts). Although many tumor cell lines undergo apoptosis when p53 is expressed, the T47D transfectants remained viable at temperatures permitting wild-type p53 phenotype. This suggested that endogenous Bcl-XL could protect cancer cells from p53-mediated apoptosis. To test this hypothesis, murine erythroleukemia cells were transfected with bcl-XL and p53ts. While cell lines expressing p53 alone rapidly died, those cells co-expressing Bcl-XL survived. These results demonstrate that Bcl-XL is capable of protecting cells from p53-mediated apoptosis, and suggest a possible mechanism by which tumors expressing Bcl-XL are able to partly overcome the tumor suppressor functions of p53.
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PMID:Bcl-XL protects cancer cells from p53-mediated apoptosis. 747 61

A rapid non-isotopic PCR-SSCP (polymerase chain reaction-single-stranded conformation polymorphism) method was developed in this study to detect polymorphism and loss of heterozygosity (LOH) of p53 in formalin-fixed and paraffin-embedded samples of normal breast tissue and of breast cancer. p53 expression was also examined by immunohistochemistry. In 35 paired samples, heterozygosity in exon 4 of p53 was detected in 17 cases (49 per cent) and LOH of the p53 gene in breast cancer tissues was observed in 7 out of 15 informative cases (47 per cent). The correlation of LOH of p53 with positive p53 immunostaining did not reach statistical significance, but all immunostaining-positive tumours among informative cases had LOH of p53. The results support the hypothesis that in most cases the allelic deletion of p53 may uncover the 'recessive mutation' in the remaining allele. However, LOH of p53 was more frequent than positive immunostaining and was significantly associated with poor differentiation of breast cancer (P < 0.05). The results suggest that the allelic deletion of p53 may also contribute to the development and progression of breast cancer by reducing the amount of normal p53 protein. These results show that non-isotopic PCR-SSCP is a simple, fast, and effective method for detecting polymorphism and LOH of the p53 gene, which is especially useful for retrospective studies.
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PMID:Detection of loss of heterozygosity of p53 gene in paraffin-embedded breast cancers by non-isotopic PCR-SSCP. 749 Jun 78

Radioimmunotherapy (RIT) in breast cancer patients using I-131-chimeric L6 (ChL6) and in human breast cancer xenografts in nude mice using Y-90-1,4,7,10-tetraazacylododecant N,N',N",N"'-tetraacetic acid-peptide ChL6 (Y-90-ChL6) has shown promise. Tumor cell response to low-dose rate (5-25 rads/h) irradiation from Y-90-ChL6 RIT, therefore, was correlated with levels of tumor cell mRNA for selected genes linked to programmed cell death (apoptosis). Three groups of 10-16 mice with 1-2 HBT 3477 xenograft tumors were treated with 100, 150, or 250 microCi Y-90-ChL6. Three tumors were taken before and two tumors each were taken 3, 6, and 24 h after injection of 150 microCi Y-90-ChL6. Tumor expression of mRNA was amplified by PCR for p53, PIC1, c-myc, and transforming growth factor-beta 1; quantitated; and standardized to N-ras. Tumors received radiation doses of 2000, 3000, and 5000 rads, respectively, for the groups of mice that received 100, 150, and 250 microCi Y-90-ChL6, and tumor regression occurred in each group, with mean tumor volumes decreased by 10, 50, and 95% at nadir after Y-90-ChL6 injection. At the highest dose level, 30% of mice had complete remissions, and no treatment deaths occurred, although tumors subsequently recurred. Continuous up-regulation of transforming growth factor-beta 1 and c-myc mRNA expression was observed from 3 to 24 h after treatment. Expression of p53 and PIC1 increased at 3 h and subsequently decreased to the untreated control levels. These observations are consistent with previous observations of early responses of p53 and PIC1 to cellular DNA damage and subsequent G1 cell cycle arrest or apoptosis. Apoptosis-associated gene expression patterns observed in this tumor model provide evidence that changes are initiated in the first 24 h of RIT associated with radiation doses of 100-700 rads. These preliminary data suggest that insight into the molecular basis of RIT-induced tumor regression may be gained by further studies using different radiation doses.
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PMID:Yttrium-90 chimeric L6 therapy of human breast cancer in nude mice and apoptosis-related messenger RNA expression. 749 56

Under normal culturing conditions, the T47D human breast cancer cell line expresses progesterone receptor constitutively and is responsive to estrogen. Because the tumor suppressor protein p53 plays a central role in determining genetic stability and cell proliferation, we have examined the effects of 17 beta-estradiol, the synthetic progestin R5020, and the antiprogestin RU486 on the levels of this protein in T47D cells. Western blot analysis of cellular extracts, performed with a monoclonal antibody capable of quantitatively supershifting a specific p53-p53 response element complex in a gel mobility shift assay, detected a single immunoreactive band representing p53. When cells were grown for 4-5 days in culture medium containing charcoal-treated fetal calf serum, p53 levels declined to 10% of the level seen in the control (no charcoal treatment) group. Supplementation of culture medium containing charcoal-treated calf serum with 0.1-1 nM 17 beta-estradiol restored p53 to its normal levels. A 4-day treatment of cells with R5020 or RU486 lowered the p53 levels in cells grown in normal culturing conditions to 15 and 30% of control levels, respectively. R5020 and RU486 treatments also caused down-regulation and/or hyperphosphorylation of the progesterone receptor, which correlated with the down-regulation of p53. These observations by estradiol while R5020 down-regulates this protein. Since estradiol is known to promote cell proliferation, the induction of p53 observed in this study leads us to propose that estradiol stimulates p53 to regulate proliferation of T47D cells in culture.
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PMID:Hormonal regulation of the p53 tumor suppressor protein in T47D human breast carcinoma cell line. 749 60

The causative factors leading to breast cancer are largely unknown. Increased incidence of breast cancer following diagnostic or therapeutic radiation suggests that radiation may contribute to mammary oncogenesis. This report describes the in vitro neoplastic transformation of a normal human mammary epithelial cell strain, 76N, by fractionated gamma-irradiation at a clinically used dose (30 Gy). The transformed cells (76R-30) were immortal, had reduced growth factor requirements, and produced tumors in nude mice. Remarkably, the 76R-30 cells completely lacked the p53 tumor suppressor protein. Loss of p53 was due to deletion of the gene on one allele and a 26-bp deletion within the third intron on the second allele which resulted in abnormal splicing out of either the third or fourth exon from the mRNA. PCR with a mutation-specific primer showed that intron 3 mutation was present in irradiated cells before selection for immortal phenotype. 76R-30 cells did not exhibit G1 arrest in response to radiation, indicating a loss of p53-mediated function. Expression of the wild-type p53 gene in 76R-30 cells led to their growth inhibition. Thus, loss of p53 protein appears to have contributed to neoplastic transformation of these cells. This unique model should facilitate analyses of molecular mechanisms of radiation-induced breast cancer and allow identification of p53-regulated cellular genes in breast cells.
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PMID:Loss of p53 protein during radiation transformation of primary human mammary epithelial cells. 751 Dec 7

Breast tumors are thought to originate, grow, and metastasize in an environment which includes steroid hormone receptors, their cognate steroid ligands, and many gene products which are regulated by steroid hormone receptor-ligand complexes. In this paper we describe highly sensitive and quantitative immunofluorometric procedures for measuring three proteins that are candidate prognostic indicators in breast cancer, namely, the p53 tumor suppressor gene product, carcinoembryonic antigen (CEA), and prostate specific antigen (PSA). These proteins were quantified in over 950 cytosolic tumor extracts along with estrogen and progesterone receptors (ER, PR). Association analysis between all five biochemical parameters revealed strong negative associations between p53 and receptors and strong positive associations between CEA and receptors. Negative associations between p53 and CEA and between CEA and PSA were also found. These associations, not quantitatively studied in previous reports, are related to each other using a hypothetical model. The observed associations may further contribute to the understanding of the biology of breast tumors.
Breast Cancer Res Treat 1994
PMID:Quantitative analysis of mutant p53 protein in breast tumor cytosols and study of its association with other biochemical prognostic indicators in breast cancer. 752 72

Prostate-specific antigen (PSA) is a glycoprotein produced by the epithelial cells of the prostate. PSA is currently used in clinical practice to facilitate diagnosis and monitoring of prostate carcinoma. The prostate is an organ that possesses androgen, estrogen, and progesterone receptors, and in this respect is similar to the breast. We postulated that breast tumors might also have the ability to produce PSA. We performed these studies on a collection of 525 tumor specimens collected for routine biochemical determination of estrogen and progesterone receptors. Using a highly sensitive immunofluorometric procedure, we measured the p53 tumor suppressor gene product and PSA. Twenty nine percent of the breast tumor extracts contained detectable levels of PSA immunoreactivity (> 0.05 microgram/L). The immunoreactive PSA content was associated with estrogen and/or progesterone receptor-positive tumors (P < 0.002). No association was found between PSA immunoreactivity and levels of the p53 tumor suppressor gene product (P = 0.37). High performance liquid chromatography and Western blot analysis revealed that the PSA immunoreactivity in the tumor had a molecular weight of 30 kDa, similar to that of seminal PSA. Immunoreactive PSA-positive tumors were associated with younger women (P = 0.012) and earlier disease stage (P = 0.064). We postulate that PSA immunoreactivity may be an additional marker of steroid hormone receptor-ligand action.
Breast Cancer Res Treat 1994
PMID:Detection of prostate-specific antigen immunoreactivity in breast tumors. 753 68

Multiple mammary epithelial cell (MEC) types are observed both in mammary ducts in vivo and in primary cultures in vitro; however, the oncogenic potential of different cell types remains unknown. Here, we used human papilloma virus 16 E6 and E7 oncogenes, which target p53 and Rb tumor suppressor proteins, respectively, to immortalize MECs present in early or late passages of human mammary tissue-derived cultures or in milk. One MEC subtype was exclusively immortalized by E6; such cells predominated in late-passage cultures but were rare at early passages and apparently absent in milk. Surprisingly, a second cell type, present only in early-passage tissue-derived cultures, was fully immortalized by E7 alone. A third cell type, observed in tissue-derived cultures and in milk, showed a substantial extension of life span with E7 but eventually senesced. Finally, both E6 and E7 were required to fully immortalize milk-derived MECs and a large proportion of MECs in early-passage tissue-derived cultures, suggesting the presence of another discrete subpopulation. Identification of MECs with distinct susceptibilities to p53- and Rb-targeting human papillomavirus oncogenes raises the possibility that these cells may serve as precursors for different forms of breast cancer.
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PMID:Immortalization of distinct human mammary epithelial cell types by human papilloma virus 16 E6 or E7. 753 74

The value of tumor angiogenesis, EGFR and c-erbB-2 oncoprotein, a long with p 53 protein expression for predicting relapse-free survival was investigated in 110 node-negative breast cancer patients. The grade of neovascularization was assessed by the microvessel density which was obtained by an immunocytochemical staining by factor VIII-related antigen. EGFR, c-erbB-2 oncoprotein and p 53 oncoprotein were also determined by immunocytochemical assay. Univariate analysis showed no statistical significance of EGFR, c-erbB-2 and p53 status as a prognostic indicator. However, the microvessel density was a significant predictor of relapse-free survival. Patients with over 100 counts of factor VIII-RA positive cells per mm2 field in the most active areas of neovascularization showed significantly poorer prognosis compared to those with less than 100 counts (p < 0.005). Multivariate analysis demonstrated that microvessel density was an independent prognostic indicator in node-negative breast cancer patients (p < 0.0005). It was suggested that microvessel density might be of use in selecting the high-risk group in node-negative breast cancer patients needing adjuvant therapies.
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PMID:[Significance of tumor angiogenesis as an independent prognostic factor in axillary node-negative breast cancer]. 753 84


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