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

Human breast cancers may overexpress certain heat shock protein (hsp) family members, proteins which are involved with cell proliferation and differentiation as well as with disease prognosis and drug resistance. Here, we have studied the relationship between the expression of two hsps (hsp27 and hsp70) and the proliferative activity of tumor cells in 40 biopsies from breast cancer patients. Twenty of these tumors were selected for a detailed colocalization study. Immunocytochemistry was done using specific antibodies against hsp27 and hsp70. Cell proliferation was studied analyzing the expression of proliferating cell nuclear antigen (PCNA) (late G1, S, and G2 phases of the cell cycle) and the number of silver-staining nucleolar organizer regions (AgNORs) (G1 phase). The colocalization study revealed a statistically significant inverse correlation between hsp27 expression and cell proliferation in 16/19 (84%) of the cases evaluated by PCNA immunostaining, and in 11/16 (69%) of the cases evaluated by AgNORs. In contrast, a statistically significant positive correlation between hsp70 expression and elevated cell proliferation was seen in almost 85% of the cases evaluated by PCNA staining, and in almost 50% of the cases evaluated by AgNORs. Moreover, in 22% (9/40) of the breast cancer samples examined, hsp70 was clearly associated with the mitotic spindle. A Western blot analysis revealed that hsp70 was coprecipitated with taxol-polymerized tubulin. The association of hsp70 with the mitotic spindle was not clearly noted in lung carcinoma samples (N = 20) or in normal cells displaying elevated mitotic activity. These studies thus demonstrate that in a significant percentage of clinical breast cancers hsp27 overexpression is inversely correlated with cell proliferation, while hsp70 is clearly associated with the mitotic spindle and cell proliferation. These results add evidence to the concept that in human breast cancers hsp27 may be involved in cell growth arrest and increased differentiation while, in contrast, hsp70 may be involved in cell proliferation; further studies will be necessary to elucidate these possible cause-and-effect relationships.
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PMID:Heat shock proteins and cell proliferation in human breast cancer biopsy samples. 930 47

Estrogen receptor (ER)-negative MDA-MB-468 human breast cancer cells were stably transfected with wild-type human ER and utilized as a model for investigating estrogen- and aryl hydrocarbon (Ah)-responsiveness. Treatment of the stably transfected cells with 10 nM 17 beta-estradiol (E2) resulted in a significant inhibition (> 60%) of cell proliferation and DNA synthesis, which was blocked by 10(-7) M ICI 182 780. Analysis by flow cytometry indicated that treatment with E2 increased the percentage of cells in G0/G1 (from 68.8 to 89.4) and decreased cells in S (from 18.4 to 3.4) and G2/M (from 12.8 to 7.2) phases of the cell cycle. The effects of E2 on the major cyclins, cyclin-dependent kinases and cyclin-dependent kinase inhibitors, retinoblastoma protein (RB), E2F-1, and cyclin-dependent kinase activities were also investigated in the stably transfected MDA-MB-468 cells. The results demonstrated that the growth inhibitory effects of 10(-8) M E2 in ER stably transfected MDA-MB-468 cells were associated with modulation of several factors required for cell cycle progression and DNA synthesis, including significant induction of the cyclin-dependent kinase inhibitor p21cip-1 ( > 4-fold increase after 12 h) and decreased E2F1 and PCNA protein levels. These results show that the growth-inhibitory effects of E2 in the stably transfected cells were due to multiple factors which result in growth arrest in G0/G1 and inhibition of DNA synthesis.
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PMID:17 beta-Estradiol-mediated growth inhibition of MDA-MB-468 cells stably transfected with the estrogen receptor: cell cycle effects. 935 72

Adipose tissue and muscle constitute the larger proportion of body mass, and therefore aromatization in these tissues is the major source of circulating estrogens in postmenopausal women. Although plasma estrogen concentrations are very low, levels in breast cancers from postmenopausal patients are reported to be 10-fold higher than in plasma and normal tissue. Whereas studies on aromatase activity in the tumor suggest that estrogen may be produced locally, the significance of this contribution has been questioned. Using immunocytochemistry (ICC) to an anti-aromatase antibody, a relatively strong immunoreaction was detected in tumor epithelial cells as well as in the terminal ductal lobular units (TDLUs) of the normal breast. Aromatase expression was detected in the cytoplasm of tumor epithelial cells and the surrounding stromal cells of over 50% of tumors in a series of 19 breast cancers. In situ hybridization (ISH) to aromatase mRNA confirmed the immunocytochemical result that the epithelial cells are the primary site of estrogen synthesis in the breast and breast cancers. In the 10 tumors which showed immunoreaction to aromatase, the average aromatase activity measured in cryosections was 286.5 +/- 18.6 fmol estrogen/mg protein/h (SE), whereas in nine tumors with weak aromatase immunoreaction, the enzyme activity was 154.7 +/- 19.3 fmol estrogen/mg protein/h (P < 0.05) (SE). The functional significance of tumor aromatase and locally produced estrogens on the growth of tumors was suggested by the correlation between aromatase activity and proliferating cell nuclear antigen (PCNA), a marker of cell proliferation (P < 0.005). Although intratumoral aromatase activity did not correlate with steroid receptors significantly, there was a trend for estrogen receptor (ER)-positive tumors to express aromatase. In addition, proliferation ([3H]-thymidine incorporation into DNA) during histoculture, was increased by both estradiol and testosterone in tumors with high aromatase activity. Our results suggest that some tumors synthesize sufficient estrogen to stimulate their proliferation. It may thus be important to inhibit tumor aromatase as well as to reduce circulating levels of estrogen for effective breast cancer treatment.
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PMID:Aromatase in the normal breast and breast cancer. 936 2

The RNA polymerase II (Pol II) holoenzyme in yeast is an essential transcriptional regulatory complex which has been defined by genetic and biochemical approaches. The mammalian counterpart to this complex, however, is less well defined. Experiments herein demonstrate that, along with Pol II and SRB proteins, proteins associated with transcriptional regulation as cofactors are associated with the Pol II holoenzyme. Earlier experiments have demonstrated that the breast cancer-associated tumor suppressor BRCA1 and the CREB binding protein (CBP) were associated with the holoenzyme complex. The protein related to CBP, the E1A-associated p300 protein, is shown in these experiments to be associated with the holoenzyme complex as well as the BRG1 subunit of the chromatin remodeling SWI/SNF complex. Importantly, the Pol II holoenzyme complex does not contain some factors previously reported as stoichiometric components of the holoenzyme complex, most notably the proteins which function in repair of damaged DNA, such as PCNA, RFC and RPA. The presence of the p300 coactivator and the chromatin-modifying BRG1 protein support a role for the Pol II holoenzyme as a key target for regulation by enhancer binding proteins.
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PMID:Factors associated with the mammalian RNA polymerase II holoenzyme. 944 79

In 87 breast cancer patients, the immunohistochemical expression of the basement membrane (BM)-degrading enzyme cathepsin D (CD) was correlated with the expression of extracellular matrix components, with growth fraction, steroid receptor content and with the other conventional prognostic variables in breast cancer. Only 6.25% of tumours had laminin-defined BM, while 86.8% showed staining for fibronectin. CD was also identified in carcinoma cells (cancer cell CD; CCCD) and in stromal cells (stromal cell CD; SCCD). Forty-five percent of tumours showed CCCD and 47.5%, SCCD expression. CCCD expression was significantly correlated with positive oestrogen receptor content, with low Ki-67 and high PCNA score and with SCCD expression. There was no correlation with collagen type IV, laminin or fibronectin. SCCD expression was positively correlated with collagen type IV, laminin expression and tumour grade. The data suggest that the CD of tumour cells and the CD of tumour-associated macrophages have different roles in breast cancer. CCCD correlates with cell proliferation and is regulated by oestrogens, while SCCD relates to cell differentiation, is oestrogen-independent, and has a proteolytic role in the breakdown of BM components.
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PMID:Immunohistochemical expression of cathepsin D in correlation with extracellular matrix component, steroid receptor status and proliferative indices in breast cancer. 946 71

The mouse homologues of the breast cancer susceptibility genes, Brca1 and Brca2, are expressed in a cell cycle-dependent fashion in vitro and appear to be regulated by similar or overlapping pathways. Therefore, we compared the non isotopic in situ hybridization expression patterns of Brca1 and Brca2 mRNA in vivo in mitotic and meiotic cells during mouse embryogenesis, mammary gland development, and in adult tissues including testes, ovaries, and hormonally altered ovaries. Brca1 and Brca2 are expressed concordantly in proliferating cells of embryos, and the mammary gland undergoing morphogenesis and in most adult tissues. The expression pattern of Brca1 and Brca2 correlates with the localization of proliferating cell nuclear antigen, an indicator of proliferative activity. In the ovary, Brca1 and Brca2 exhibited a comparable hormone-independent pattern of expression in oocytes, granulosa cells and thecal cells of developing follicles. In the testes, Brca1 and Brca2 were expressed in mitotic spermatogonia and early meiotic prophase spermatocytes. Northern analyses of prepubertal mouse testes revealed that the time course of Brca2 expression was delayed in spermatogonia relative to Brca1. Thus, while Brca1 and Brca2 share concordant cell-specific patterns of expression in most proliferating tissues, these observations suggest that they may have distinct roles during meiosis.
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PMID:Brca1 and Brca2 expression patterns in mitotic and meiotic cells of mice. 946 43

Women who bear their first child by their late teens have about half the risk of developing breast cancer relative to nulliparous women. The rat is a good model for studying the role of hormones in breast cancer since, for example, young rats become nearly refractory to mammary carcinogenesis after delivering a litter of pups. Short term administration of estradiol and progesterone (E & P) provides virgin rats protection from mammary carcinogenesis as effectively as pregnancy. The purpose of these studies were twofold: first, to evaluate potential long-term toxicity of the E & P treatments and second, to compare hormone treated rats and pregnant rats with respect to circulating E & P levels as well as mammary epithelial cell proliferation and differentiation. To test for toxicity, rats were treated with E & P (20 micrograms and 4 mg, respectively) or vehicle by s.c. injections 5 times per week for 5 weeks beginning at 40 days of age. The animals were weighed biweekly and sacrificed at 500 days of age when detailed necropsies were performed. No significant difference in weight gain was observed between the two groups nor was any toxicity grossly observable in the hormone-treated rats. Furthermore, there was no increase in the number of spontaneous mammary or pituitary tumors in the E & P treated group relative to controls. To evaluate serum hormone titers and mammary proliferation, rats were treated with steroids or vehicle daily beginning at 65 days of age. At 6 and 24 hours after the 1st, 14th and 35th injection, serum E & P were measured by RIA and mammary epithelial cell proliferation by immunohistochemistry (PCNA). At 6 hours after each injection, E & P levels were 3 to 5 fold those observed late in pregnancy. By 24 hours, however, E & P levels subsided to late pregnancy levels or lower. The mammary epithelial cell proliferation index in either E & P treated or late pregnant rats was 6 to 14%. Histologic sections and wholemounts of mammary glands showed a similar degree of differentiation between rats treated with E & P for 14 days or longer and late pregnant rats. These data further suggest that E & P treatments are a non-toxic means of mimicking the protective effect of pregnancy against mammary cancer and that pregnancy or hormone treatments may achieve this prophylaxis through a differentiation mechanism.
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PMID:Hormone levels and mammary epithelial cell proliferation in rats treated with a regimen of estradiol and progesterone that mimics the preventive effect of pregnancy against mammary cancer. 949 82

1,25-Dihydroxyvitamin D3 [1,25-(OH)2D3] and its synthetic analog EB1089 induce characteristic morphological features of apoptosis in MCF-7 cells in vitro that coincide with up-regulation of clusterin and cathepsin B, proteins associated with apoptosis in the mammary gland, and with down-regulation of Bcl-2, an antiapoptotic protein. To determine whether vitamin D3 compounds could mediate apoptosis of breast tumors in vivo, we treated nude mice carrying established MCF-7 xenografts with the low calcemic vitamin D3 analog EB1089 via daily injection or sustained release pellets for up to 5 weeks. The volume of tumors from mice treated with 45 pmol/day EB1089 was 4-fold lower than that of tumors from vehicle-treated control mice after 5 weeks. The reduced growth of tumors from EB1089-treated mice was associated with characteristic apoptotic morphology and a marked reduction in the proportion of epithelial cells to stroma. After 5 weeks of treatment with EB1089, MCF-7 tumors exhibited a 6-fold increase in DNA fragmentation (as measured by in situ end labeling) relative to that in control tumors. The enhanced rate of apoptosis in tumors from EB1089-treated mice was coupled to a 2-fold reduction in proliferation (as measured by expression of proliferating cell nuclear antigen) compared with that in tumors from control mice. The antitumor effects of EB1089 were evident at doses that had minimal effects on serum calcium and body weight. EB1089 treatment did not alter the growth of xenografts derived from a vitamin D3-resistant variant of MCF-7 cells (MCF-7(D3Res) cells), which display resistance to EB1089 in vitro, indicating that resistance to EB1089 is maintained in vivo. Tumors derived from both MCF-7 and MCF-7(D3Res) cells underwent apoptotic regression upon estradiol withdrawal, indicating comparable estrogen dependence of tumors with differential sensitivity to vitamin D3 compounds. These are the first studies to demonstrate apoptotic morphology and regression of human breast tumors in response to treatment with a vitamin D3 analog in vivo and support the concept that vitamin D3 compounds can effectively target human breast cancer.
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PMID:Apoptotic regression of MCF-7 xenografts in nude mice treated with the vitamin D3 analog, EB1089. 952 99

Cell proliferation was evaluated in 167 tissue specimens obtained from primary breast cancer patients who had undergone radical surgery between 1984 and 1988. Formalin-fixed and paraffin-embedded tissue specimens were used in the immunohistochemical study. The immunohistochemical method was carried out using the avidin-biotin immunoperoxidase technique, and anti-proliferating cell nuclear antigen (PCNA) monoclonal antibody was used for primary antibody. Based upon the PCNA labeling index (LI), the patients were divided into two groups: low PCNA, <25% and high PCNA, >/= 25%. The PCNA LI ranged from 1% to 76% (mean, 23.9%). Patients aged </= 50 showed significantly higher PCNA LI than those of > 50 years. There was no relationship between the PCNA LI and tumor size, lymph node involvement and hormone receptors. The survival curves of 146 invasive breast cancer patients showed that the high PCNA group had poor overall survival compared with the low PCNA group. A significant difference in the overall survival between the high and low PCNA groups was observed in lymph node-positive patients, however, no significant difference was found between the two groups in lymph node-negative patients. PCNA LI was identified as an independent predictor in primary breast cancer patients.
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PMID:Long-term prognostic value of PCNA labeling index in primary operable breast cancer. 953 67

We have previously described the isolation and characterization of an intact multiprotein complex for DNA replication, designated the DNA synthesome, from human breast cancer cells and biopsied human breast tumor tissue. The purified DNA synthesome was observed to fully support DNA replication in vitro. We had also proposed a model for the breast cell DNA synthesome, in which DNA polymerases alpha, delta, and epsilon, DNA primase, and replication factor C (RF-C) represent members of the core component, or tightly associated, proteins of the complex. This model was based on the observed fractionation, chromatographic, and sedimentation profiles for these proteins. We report here that poly(ADP-ribose)polymerase (PARP) and DNA ligase 1 are also members of the breast cell DNA synthesome core component. More importantly, in this report we present the results of coimmunoprecipitation studies that were designed to map the protein-protein interactions between several members of the core component of the DNA synthesome. Consistent with our proposed model for the breast cell DNA synthesome, our data indicate that DNA polymerases alpha and delta, DNA primase, RF-C, as well as proliferating cell nuclear antigen (PCNA), tightly associate with each other in the complex, whereas DNA polymerase epsilon, PARP, and several other components were found to interact with the synthesome via a direct contact with only PCNA or DNA polymerase alpha. The association of PARP with the synthesome core suggests that this protein may serve a regulatory function in the complex. Also, the coimmunoprecipitation studies suggest that the three DNA polymerases alpha, delta, and epsilon all participate in the replication of breast cell DNA. To our knowledge this is the first report ever to describe the close physical association of polypeptides constituting the intact human breast cell DNA replication apparatus.
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PMID:Mapping specific protein-protein interactions within the core component of the breast cell DNA synthesome. 956 11


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