UMLS:C0006142 - FACTA Search

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

A methodology recently developed by the U.S. EPA for estimating the carcinogenic risks from ionizing radiation is described. For most cancer sites, the risk model is one in which age-specific, relative risk coefficients are obtained by taking a geometric mean of the coefficients derived from the atomic bomb survivor data using two different methods for transporting risks from the Japanese to the U.S. population. The risk models are applied to estimate organ-specific risks per unit dose for a stationary population with mortality rates governed by 1980 U.S. vital statistics. With the exception of breast cancer, low-LET radiogenic cancer risk estimates are reduced by a factor of 2 at low doses and dose rates compared to acute high dose exposure conditions. For low dose (or dose rate) conditions, the risk of inducing a premature cancer death from uniform, whole body, low-LET irradiation is calculated to be 5.1 x 10(-2) Gy-1. Neglecting nonfatal skin cancers, the corresponding incidence risk is 7.6 x 10(-2) Gy-1. High-LET (alpha particle) risks are presumed to increase linearly with dose and to be independent of dose rate. High-LET risks are estimated to be 20 times the low-LET risks estimated under low dose rate conditions, except for leukemia and breast cancer where RBEs of 1 and 10 are adopted, respectively.
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PMID:Estimates of radiogenic cancer risks. 779 Feb 17

Essential fatty acids (EFAs) cannot be synthesized by mammalian cells. Once taken in with the diet, they can undergo desaturations/saturations and chain elongations/shortenings to yield a variety of polyunsaturated fatty acids of the same family. Cells in vitro from a variety of tissues are capable of processing EFAs to varying extents. Conversion of the parent EFAs, linoleic (LA, n-6) and alpha-linolenic (LNA, n-3) acids, to the 20-carbon polyunsaturated fatty acids, arachidonic (AA, n-6) and eicosapentanoic (EPA, n-3), requires chain elongation and delta 6 and delta 5 desaturations. AA and EPA are required by many tissues for optimal biological function and are precursors of biologically active eicosanoid hormones. All cultured cells are able to elongate exogenous LA and LNA, and most can perform delta 5 desaturation, so delta 6 desaturation is the limiting step in AA and EPA production. Longer fatty acids that have more double bonds than AA or EPA are less frequently produced due to a deficiency in delta 4 desaturating ability. The process of retroconversion (chain shortening) is less extensively studied, but evidence from a variety of cells suggests that this type of metabolic conversion is normally active. The example of MCF-7 (human breast cancer cell line) and MCF-10A cells (human noncancerous breast cell line) is discussed in order to emphasize the diversity in EFA processing ability of cultured cells. Under identical culture conditions, MCF-10A cells perform extensive desaturations, elongations, and retroconversions, whereas MCF-7 cells can only elongate and retroconvert exogenous EFAs. Given the great diversity in the ability of cultured cells to process EFAs, no conclusions can be drawn regarding the mechanisms responsible for the effects of exogenous EFAs on a particular cell until that cell's EFA processing patterns have been evaluated.
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PMID:Diversity in the ability of cultured cells to elongate and desaturate essential (n-6 and n-3) fatty acids. 783 35

The type rather than the amount of dietary fat may be more important in breast carcinogenesis. While animal studies support this view, little is known about the effects of essential fatty acids (EFAs) at the cellular level. The MCF-7 breast cancer and the MCF-10A non-cancerous human mammary epithelial cell lines are compared in terms of growth response to EFAs and ability to incorporate and process the EFAs. Eicosapentaenoic (EPA, n-3) and docosahexaenoic (DHA, n-3) acids, presented bound to albumin, inhibited the growth of MCF-7 cells by as much as 50% in a dose-dependent manner (6-30 microM) in medium containing 0.5% serum. alpha-Linolenic (LNA, n-3) and arachidonic (AA, n-6) acids inhibited growth less extensively, while linoleic acid (LA, n-6) had no effect. In contrast, MCF-10A cells were not inhibited by any of the EFAs at levels below 24 microM. The differential effects of AA, EPA and DHA on MCF-7 and MCF-10A cells support a protective role of highly unsaturated essential fatty acids against breast cancer. The EFAs were primarily incorporated into phosphoglycerides. MCF-7 cells showed chain elongations and possibly delta 8 desaturation, but no AA was formed from LA, nor EPA or DHA from LNA. In contrast, MCF-10A cells desaturated and elongated the exogenous EFAs via all the known pathways. These findings suggest defects in the desaturating enzymes of MCF-7 cells. LNA, DHA and AA presented to MCF-7 cells in phospholipid liposomes inhibited growth as extensively as albumin-bound free acids, but were less extensively incorporated, suggesting different mechanisms of inhibition for the two methods.
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PMID:n-3 and n-6 fatty acid processing and growth effects in neoplastic and non-cancerous human mammary epithelial cell lines. 805 69

Matrix metalloproteinase (MMP) family members have been associated with advanced-stage cancer and contribute to tumor progression, invasion, and metastasis as determined by inhibitor studies. In situ hybridization was performed to analyze the expression and localization of all known MMPs in a series of human breast cancer biopsy specimens. Most MMPs were localized to tumor stroma, and all MMPs had very distinct expression patterns. Matrilysin was expressed by morphologically normal epithelial ducts within tumors and in tissue from reduction mammoplasties, and by epithelial-derived tumor cells. Many family members, including stromelysin-3, gelatinase A, MT-MMP, interstitial collagenase, and stromelysin-1 were localized to fibroblasts of tumor stroma of invasive cancers but in quite distinct, and generally widespread, patterns. Gelatinase B, collagenase-3, and metalloelastase expression were more focal; gelatinase B was primarily localized to endothelial cells, collagenase-3 to isolated tumor cells, and metalloelastase to cytokeratin-negative, macrophage-like cells. The MMP inhibitor, TIMP-1, was expressed in both stromal and tumor components in most tumors, and neither stromelysin-2 nor neutrophil collagenase were detected in any of the tumors. These results indicate that there is very tight and complex regulation in the expression of MMP family members in breast cancer that generally represents a host response to the tumor and emphasize the need to further evaluate differential functions for MMP family members in breast tumor progression.
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PMID:Expression of most matrix metalloproteinase family members in breast cancer represents a tumor-induced host response. 868 51

The tissue inhibitors of metalloproteinases (TIMPs) constitute a family of proteins, of which three members have so far been described. Using the expressed sequence tag sequencing approach, we have identified a novel TIMP-related cDNA fragment and subsequently cloned a fourth human TIMP (TIMP-4) from a human heart cDNA library. The open reading frame encodes a 224-amino acid precursor including a 29-residue secretion signal. The predicted structure of the new protein shares 37% sequence identity with TIMP-1 and 51% identity with TIMP-2 and -3. The protein has a predicted isoelectric point of 7.34. The open reading frame-directed expression of TIMP-4 protein in MDA-MB-435 human breast cancer cells showed metalloproteinase inhibitory activity on reverse zymography. By Northern analysis, only the adult heart showed abundant TIMP-4 transcripts with a 1. 4-kilobase predominant transcript band; very low levels of the transcripts were detected in the kidney, placenta, colon, and testes, and no transcripts were detected in the liver, brain, lung, thymus, and spleen. This unique expression pattern suggests that TIMP-4 may function in a tissue-specific fashion in extracellular matrix homeostasis.
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PMID:Molecular cloning and characterization of human tissue inhibitor of metalloproteinase 4. 893 99

An intact basement membrane is essential for the proper function, differentiation and morphology of many epithelial cells. The disruption or remodeling of the basement membrane occurs during normal development as well as in the disease state. Stromelysin-1 (SL-1), a member of the matrix metalloproteinase (MMP) family, was one of the first proteinases found to be associated with cancer. In this review we describe the role of MMPs in normal mammary gland involution. To examine the importance of basement membrane during development in vivo, we altered the MMP and tissue inhibitor of metalloproteinases (TIMP) balance in mammary gland. Inhibition of MMP synthesis by glucocorticoids or implants or transgenic overexpression of TIMP-1 delays matrix degradation and the involution process after weaning. The mammary glands from transgenic mice that inappropriately express autoactivating isoforms of SL-1 are both functionally and morphologically altered throughout development. Transgenic mammary glands have supernumerary branches, and show precocious development of alveoli that express beta-casein expression and undergo unscheduled apoptosis during pregnancy. This is accompanied by progressive development of an altered stroma, which resembles that of a wound site or a tumor, and becomes fibrotic after postweaning involution, and by development of neoplasias. These data suggest that MMPs and disruption of the basement membrane may play key roles in branching morphogenesis of mammary gland, apoptosis, and stromal fibrosis as well as in induction and progression of breast cancer. These observations suggest that SL-1 and other MMPs may be useful targets for therapeutic intervention in cancer.
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PMID:Extracellular matrix remodeling as a regulator of stromal-epithelial interactions during mammary gland development, involution and carcinogenesis. 918 Oct 50

Hormone-independent growth and invasiveness represent phenotypic properties acquired during early progression of breast cancer. We compared human mammary adenocarcinoma cells, MCF-7, which are estrogen-dependent and poorly metastatic, with the estrogen-independent and highly metastatic subline, MCF7/LCC1, with regard to expression of tissue-degrading factors of the matrix metalloproteinase (MMP)-and urokinase (uPA)-dependent degradative pathways, as well as for their in vitro invasive properties. Both cell lines showed low constitutive mRNA expression of the MMP inhibitor TIMP-1. Baseline expression of TIMP-2 mRNA was also very low in MCF-7 cells, whereas the MCF7/LCC1 level was much higher (approximately 10-fold). Furthermore, both cell lines revealed low constitutive capacity to migrate in an in vitro invasion assay. Treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA; 100 nM) induced the mRNAs for TIMP-1 as well as for MMP-1, MMP-9, the uPA receptor, and the uPA inhibitor PAI-1, amongst which only the responses of MMP-9 and PAI-1 were cell-specific. The mRNA levels of MMP-9 and PAI-1 were approximately 10-fold and approximately 15-fold higher in MCF7/LCC1 cells compared to MCF-7 cells. The secretion of immunoreactive PAI-1 was considerably elevated (> 20-fold) in TPA-treated MCF7/LCC1 cells, whereas the TPA-dependent level of 92-kDa MMP-9 was only approximately 2-fold higher in MCF7/LCC1 cells than in MCF-7 cells. In both cell lines treatment with TPA was associated with an increase (approximately 10-fold) in in vitro migration, which in the MCF7/LCC1 cells was significantly attenuated by a reconstituted basement membrane extract (Matrigel). These data suggest that TPA-responsive in vitro invasive properties that are probably associated with PAI-1 expression may co-vary with progression from hormone-dependent to -independent breast cancer.
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PMID:Regulation of tissue-degrading factors and in vitro invasiveness in progression of breast cancer cells. 956 38

Genistein, a natural flavone compound, has been proposed to be responsible for the lower rate of breast cancer in Asian women. The cellular mechanisms of genistein's inhibition of breast cancer progression are largely unknown. In a previous study our laboratory has presented evidence that genistein inhibits cell proliferation of breast carcinoma cells, an inhibition which is associated with a specific G2/M arrest, induction of p21WAF/CIP1 expression and apoptosis. In the present study, we present experimental evidence that illustrates that the actions of genistein are not limited to anti-proliferation: we show that genistein can inhibit both constitutive as well as epidermal growth factor (EGF)-stimulated invasion in estrogen receptor (ER)-negative human breast carcinoma lines, MDA-MB-231 and MDA-MB-468. This inhibition is characterized by the down regulation of MMP-9 (92 kDa type IV collagenase) and up regulation of TIMP-1 (tissue inhibitor of metalloproteinases) and the trypsin inhibitors: protease nexin-II (PN-II) and alpha 1-antitrypsin (alpha 1-AT). The in vivo actions of genistein may therefore extend beyond those traditionally implicated in chemoprevention, e.g., antiproliferation; genistein may act in vivo by blocking additional stages of breast cancer progression such as those stages resulting in invasion and metastasis.
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PMID:Genistein inhibits both constitutive and EGF-stimulated invasion in ER-negative human breast carcinoma cell lines. 967 52

To evaluate the effects of dietary fats on breast cancer growth and metastasis, KPL-1 human breast carcinoma cells which have a propensity for axillary lymph node metastasis when inoculated into the thoracic mammary fat pad of female nude mice were examined. The mice were fed one of three semipurified diets containing 9.5% eicosapentaenoic acid plus 0.5% linoleic acid (EPA diet), 10% linoleic acid (LA diet), or 9.5% palmitic acid plus 0.5% linoleic acid (PA diet), or commercial laboratory chow containing 8.5% fat of which 4.1% was LA, 1.1% was PA, 0.06% was EPA, and 3.24% was other (Standard diet) starting 19 days before tumor cell inoculation and continuing until the end of the experiment (43 days after tumor cell inoculation). The tumor growth was faster and at a higher incidence in the mice fed the LA diet, and much slower and at a lower incidence in the EPA diet group compared with the mice fed the PA or Standard diet; the two separate experiment demonstrated identical results. The differences in tumor weight between the LA and PA groups and between the PA and EPA groups were significant (P < 0.05, respectively) at the termination of the experiment; the differences were due to different tumor cell proliferation rates. In an in vitro MTT assay, fatty acids showed direct stimulatory or inhibitory effects on the KPL-1 cells. Lymph node metastasis was seen in the LA and Standard diet groups, whereas it was not seen in the PA or EPA groups. The body weights were significantly lighter in the LA and EPA groups compared with the PA and Standard diet groups (P < 0.05, respectively). The results indicate that the EPA diet produced a reduction in tumor cell growth and metastasis whereas the LA diet had an enhancing effect on these parameters; dietary fatty acids may thus have a direct role in the growth and metastasis of human breast carcinoma independent of their systemic effects.
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PMID:Dietary effects of fatty acids on growth and metastasis of KPL-1 human breast cancer cells in vivo and in vitro. 967 80

In a murine model of breast cancer, IL-12 therapy exerts potent anti-angiogenic effects which contribute to tumor regression. After 7 days of treatment, levels of tumor VEGF protein decline markedly and are undetectable at 14 days. This decline is accompanied by a fall in MMP-9 and, as the tumors regress, an increase in its natural inhibitor, TIMP-1. A cell line established from the primary tumor produced VEGF in vitro. IFN-gamma reduced tumor cell production of VEGF over a 24-hr period in vitro, suggesting that IL-12-induced IFN-gamma may be responsible for the decline in VEGF levels in vivo. There is also in vitro evidence that IL-12 regulates stromal cell interactions, leading to decreased MMP-9 and increased TIMP-1 production. Thus, we suggest that at least 2 mechanisms are involved in IL-12 regulation of angiogenesis, removing the pro-angiogenic stimulus and blocking the release and activity of MMPs.
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PMID:IL-12 regulates VEGF and MMPs in a murine breast cancer model. 976 72

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