Mammaglobin expression in primary, metastatic, and occult breast cancer.
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The mammaglobin gene encodes a novel, breast cancer-associated glycoprotein. In this study, we have evaluated the frequency with which mammaglobin expression can be detected in primary and metastatic breast tumors and in breast tumor cells present in the peripheral circulation. Of 100 primary human breast tumors examined, 81 were strongly immunopositive for mammaglobin protein. Staining was independent of tumor grade and histological type. Ten of 11 lymph nodes from patients with metastatic breast cancer contained detectable mammaglobin mRNA, whereas mammaglobin expression in uninvolved lymph nodes was undetectable. Using a nested reverse transcription-PCR assay, mammaglobin mRNA was also detected in 9 of 15 products (60%) used for autologous stem cell transplant. These results suggest that larger clinical studies are warranted to investigate the full clinical utility of mammaglobin as a tool for breast cancer patient management. (+info)
Isolation of a novel gene, TSP50, by a hypomethylated DNA fragment in human breast cancer.
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A novel gene, testes-specific protease 50 (TSP50), was isolated from a human testes cDNA library by using a genomic DNA probe, BR50. BR50 was isolated by a modified representational difference analysis (RDA) technique due to its hypomethylated feature in a breast cancer biopsy. This altered DNA methylation status was also detected by BR50 in other breast and some ovarian cancer tissues. The TSP50 gene product is a homologue to several human proteases, which indicates that it may encode a protease-like protein. Northern analysis of 16 different types of normal human tissues suggests that TSP50 was highly and specifically expressed in human testes, which indicates that it might possess a unique biological function(s) in that organ. Methylation status analysis in normal human testes and other tissues showed a correlation between DNA methylation and gene expression. Most importantly, reverse transcription-PCR analysis of 18 paired breast cancer tissues found that in 28% of the cancer samples, the TSP50 gene was differentially expressed. The possibility that TSP50 may be an oncogene is presently under investigation. (+info)
Presence of tumor DNA in plasma of breast cancer patients: clinicopathological correlations.
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Using different molecular techniques, DNA has been detected in the plasma of cancer patients with various types of tumors. We undertook the present study to investigate the presence of plasma DNA, before mastectomy, in patients with breast cancer at diagnosis and to analyze the clinicopathological spectrum of this subgroup of patients with respect to patients without DNA with tumor characteristics. We studied 62 patients with breast cancer, who were selected sequentially after mastectomy and diagnosis of breast carcinomas. Genomic DNA extracted from tumor and normal tissues, normal blood cells, and plasma was used for molecular studies. Alterations in polymorphic markers selected because they had been found to show a high rate of alterations in breast cancer in previous studies (D17S855, D17S654, D16S421, TH2, D10S197, and D9S161), as well as mutations in the p53 gene and aberrant methylation at the first exon of p16INK4a, were used to identify and characterize tumor and plasma DNA. Thirteen clinicopathological parameters were analyzed in each patient. We identified 56 cases (90%) with at least one molecular event in tumor DNA, and 41 cases (66%) with a similar alteration in plasma DNA. Comparison of the clinicopathological parameters between patients with and without plasma DNA revealed significant differences in the axillary involvement, rate of invasive ductal carcinoma, high proliferative index, and the parameter comprised of lymph node metastases, histological grade II, and peritumoral vessel involvement. A high proportion of breast cancer patients exhibited plasma DNA at diagnosis similar to tumor DNA, and its presence correlated significantly with pathological parameters associated with a poor prognosis. (+info)
Altered expression of exon 6 deleted progesterone receptor variant mRNA between normal human breast and breast tumour tissues.
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The progesterone receptor (PR) is an important prognostic marker in breast cancer as well as a marker of responsiveness to endocrine therapies. The presence of several exon-deleted PR variant mRNAs in both normal and neoplastic breast samples has recently been reported. Amongst them, a variant mRNA deleted in exon 6 (D6-PR mRNA) that if translated would encode a truncated PR-like protein missing the hormone binding domain and one of the transactivating domains of the wild-type PR protein. In order to determine whether changes in D6-PR variant expression could occur during tumorigenesis, its expression was investigated by reverse transcription and polymerase chain reaction in ten normal reduction mammoplasty samples, nine breast tumours with high PR levels (> 100 fmol mg(-1) protein) and eight breast tumours with low PR levels (< 15 fmol mg(-1) protein), as determined by ligand binding assay. The relative expression of D6-PR to wild-type PR mRNA was lower (P< 0.01 ) in normal than in all tumour breast samples. Moreover, a trend to lower (P < 0.1) relative D6-PR expression was observed in high PR tumours, compared to low PR tumours. These data suggest that increased expression of D6-PR occurs during tumorigenesis. (+info)
Progressive region-specific de novo methylation of the p16 CpG island in primary human mammary epithelial cell strains during escape from M(0) growth arrest.
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CpG island methylation plays an important role in normal cellular processes, such as genomic imprinting and X-chromosome inactivation, as well as in abnormal processes, such as neoplasia. However, the dynamics of de novo CpG island methylation, during which a CpG island is converted from an unmethylated, active state to a densely methylated, inactive state, are largely unknown. It is unclear whether the development of de novo CpG island methylation is a progressive process, in which a subset of CpG sites are initially methylated with a subsequent increase in methylation density, or a single event, in which the initial methylation event encompasses the entire CpG island. The tumor suppressor gene p16/CDKN2a/INK4a (p16) is inactivated by CpG island methylation during neoplastic progression in a variety of human cancers. We investigated the development of methylation in the p16 CpG island in primary human mammary epithelial cell strains during escape from mortality stage 0 (M(0)) growth arrest. The methylation status of 47 CpG sites in the p16 CpG island on individual DNA molecules was determined by sequencing PCR clones of bisulfite-treated genomic DNA. The p16 CpG island was initially methylated at a subset of sites in three discrete regions in association with p16 transcriptional repression and escape from M(0) growth arrest. With continued passage, methylation gradually increased in density and methylation expanded to sites in adjacent regions. Thus, de novo methylation in the p16 CpG island is a progressive process that is neither site specific nor completely random but instead is region specific. Our results suggest that early detection of methylation in the CpG island of the p16 gene will require methylation analysis of the three regions and that the identification of region-specific methylation patterns in other genes may be essential for an accurate assessment of methylation-mediated transcriptional silencing. (+info)
Carcinoma of the axillary breast.
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Axillary breast is one of the varieties of polymastia which is characterized by the presence of more than 2 breasts. It may cause symptoms during pregnancy, lactation, or in the premenopausal period. Unless there are obvious symptoms of lactation or the assistance of further imaging studies such as mammography and breast ultrasound, the diagnosis is often confused with subcutaneous lipoma. The incidence of axillary breast cancer is low but it should be investigated and treated properly in view of another breast cancer in the embryonic milk-line. In this paper we reviewed 4 cases of axillary breast cancer and documented some articles regarding aberrant breast and carcinoma arising from it. It is suggested that subcutaneous nodules of uncertain origin around the periphery of the breast should be viewed with suspicion and treated properly. (+info)
Enhanced apoptotic response to photodynamic therapy after bcl-2 transfection.
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Apoptosis is a cellular death process involving the sequential activation of a series of caspases, endonucleases, and other enzymes. The initiation of apoptosis can be inhibited by overexpression of bcl-2 and certain other members of a related family of proteins. We examined the effects of bcl-2 overexpression on the apoptotic response to photodynamic therapy (PDT), using aluminum phthalocyanine as the photosensitizing agent. In this study, we compared the immortalized human breast epithelial cell line MCF10A with a subline (MCF10A/bcl-2) transfected with the human bcl-2 gene. The latter was approximately 2-fold more sensitive to the phototoxic effects of PDT. At a 50 mJ/cm2 light dose, photodamage to MCF-10A/bcl-2 resulted in a greater loss of the mitochondrial membrane potential (delta(psi)m), enhanced release of mitochondrial cytochrome c, a more rapid and greater activation of caspase-3, and a greater apoptotic response. Western blot analysis revealed that the transfected cell line showed overexpression of both bcl-2 and bax, and that PDT caused selective destruction of bcl-2, leaving bax unaffected. The greater apoptotic response by the transfected line is, therefore, attributed to the higher bax:bcl-2 ratio after photodamage. (+info)
Functional culture models to study mechanisms governing apoptosis in normal and malignant mammary epithelial cells.
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Mammary tissue homeostasis depends upon dynamic interactions between the epithelial cells, their microenvironment (including the basement membrane and the stroma), and the tissue architecture, which influence each other reciprocally to regulate growth, death and differentiation in the gland. To study how apoptosis is regulated in normal mammary cells, and to understand its role in breast tumor pathogenesis, we need model systems that recapitulate breast tissue architecture and microenvironment in culture. We have established culture models of primary and established nonmalignant mammary cell lines from both rodent and human, and defined procedures to study how cell and tissue architecture affect signaling by the basement membrane. We show that both a basement membrane and an organized tissue structure are required to achieve sustained mammary cell survival. These models could now be used to investigate how the basement membrane represses apoptosis in normal cells, and how breast cancers become death-resistant. (+info)