Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Synthesis of the biologically active oestrogen, oestradiol, within breast tumours makes an important contribution to the high concentrations of oestrogens which are present in malignant breast tissues. In breast tumours, oestrone is preferentially converted to oestradiol by the Type I oestradiol 17 beta-hydroxysteroid dehydrogenase (E2DH). Several growth factors, such as insulin-like growth factor Type I, and cytokines, such as Tumour Necrosis Factor alpha (TNF alpha), have been shown to stimulate E2DH activity in MCF-7 breast cancer cells. As little is known about the regulation of Type I E2DH expression and activity in other breast cancer cell lines, the expression and activity of this enzyme was examined in other oestrogen receptor positive and also oestrogen receptor negative breast cancer cell lines. As it is possible that E2DH activity may be limited by co-factor availability, the effects of exogenous co-factors on enzyme activity in these cell lines was also investigated. For T47D and BT20 breast cancer cells, the addition of exogenous co-factors was found to enhance enzyme activity. TNF alpha, in addition to stimulating E2DH activity in MCF-7 cells, also increased activity in T47D and MDA-MB-231 cells, although to a lesser extent than in MCF-7 cells. An investigation of signalling pathways involved in the regulation of E2DH activity revealed that stimulation of both the protein kinase C (PKC) and PKA pathways may be involved in regulation of E2DH activity. As several growth factors and cytokines have now been found to be involved in regulating E2DH activity, the role that macrophages and lymphocytes have in supplying these factors and the mechanism by which these factors may stimulate tumour growth, is also reviewed.
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PMID:The role and proposed mechanism by which oestradiol 17 beta-hydroxysteroid dehydrogenase regulates breast tumour oestrogen concentrations. 854 83

There has been increased interest in the last few years in seeking a better understanding of the local regulation of polypeptide growth factors by systemic hormones, such as sex steroids and by polypeptide hormones. Growth factors and systemic hormones play pivotal roles in hormone-regulated cancers such as breast cancer. In this review, we discuss the regulation of members of the epidermal growth factor (EGF) family by sex steroids and by regulators of the polypeptide hormone signal transduction enzyme termed protein kinase C (PKC). Regulation of the EGF family of genes will be discussed as a model system to evaluate interactions between these two important types of regulatory pathways in breast cancer.
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PMID:Dual regulation of the epidermal growth factor family of growth factors in breast cancer by sex steroids and protein kinase C. 864 7

Nonsteroidal agent tamoxifen (Tam), a therapeutic/chemopreventive agent for breast cancer, inhibits protein kinase C (PKC), which is considered to be one of its extra-estrogen receptor sites of action. This drug is required at higher (>100 microM) concentrations to inhibit PKC in the test tube, whereas it is required at lower (1-10 microM) concentrations to induce inhibition of cell growth in estrogen receptor-negative cell types. To identify additional mechanisms of action of Tam on PKC and cell growth, studies with MDA-MB-231, an estrogen receptor-negative breast carcinoma cell type, have been carried out. Upon treatment with 5-20 microM Tam, a cytosol to membrane translocation of PKC occurred within 30 min, which was then followed by a down-regulation of the enzyme within 2 h. A transient generation of Ca2+/lipid-independent activated form of PKC was observed during this period. Rapidly growing cells require nearly 2-3-fold lower concentrations (2-5 microM) of Tam than do confluent cells to induce changes in PKC. Furthermore, phorbol ester binding observed with intact cells also decreased in Tam-treated cells only under the conditions PKC was inactivated. Unlike phorbol esters, Tam did not directly support the membrane association of PKC. The release of arachidonic acid correlated with the PKC membrane translocation. Studies carried out with [3H]Tam revealed that Tam partitioned into the membrane, and there was no appreciable covalent association of [3H]Tam with cellular proteins within this limited time period (2 h). Various antioxidants (vitamin E, vitamin C, beta-carotene, catalase, and superoxide dismutase) inhibited all these cellular effects of Tam. Moreover, vitamin E strikingly blocked Tam-induced growth inhibition. To determine whether oxymetabolites of Tam can affect PKC permanently, OH-Tam was tested with purified PKC. In contrast to Tam, which reversibly inhibited PKC, OH-Tam permanently inactivated the enzyme by modifying the catalytic domain at lower concentrations. The vicinal thiols present within this domain were found to be required to induce this inactivation. This effect was partially blocked by various antioxidants. This is the first report showing the role of oxidative stress in mediating the actions of Tam. Taken together these results suggest that Tam, by initially partitioning into the membranes, induces a generation of transmembrane signals and an oxidative stress to elicit the membrane association of PKC, followed by an irreversible activation, and subsequent down-regulation of this enzyme, which, in part, may lead to cell growth inhibition.
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PMID:Tamoxifen modulates protein kinase C via oxidative stress in estrogen receptor-negative breast cancer cells. 866 63

Mutual interactions between 17 beta-estradiol (E2) and insulin or insulin-like growth factor-I (IGF-1) in the regulation of ornithine decarboxylase (ODC) expression were examined in estrogen-responsive MCF-7 human breast cancer cells. Whereas E2 only retarded the rapid decay of ODC activity observed upon mitogen withdrawal, both insulin and IGF-1 led to a rapid (< 4 h), net increase in ODC activity that was mediated, at least in part, through their cognate receptors. E2 synergistically potentiated the induction of ODC by IGF-1, resulting in a 170-fold elevation of enzyme activity after 48 h, as compared with 23- and 70-fold increases caused by E2 and IGF-1 alone, respectively. Cooperativity was more pronounced at suboptimal peptide concentrations due to a decrease in the half-maximal concentration of insulin or IGF-1 required for ODC induction. Phorbol-12-myristate-13-acetate (PMA) also strongly induced ODC activity in a transient manner, and additively to the effect of IGF-1. IGF-1 and PMA additively increased ODC mRNA level, whereas E2 alone had no effect on ODC mRNA abundance. IGF-1 increased the half-life of ODC activity by 60%, whereas E2 or PMA alone had no significant effect on enzyme stability. On the other hand, the simultaneous addition of IGF-1 and either E2 or PMA cooperatively reduced ODC turnover, resulting in 3.5- and 2-fold increases, respectively, in the half-life of ODC activity. Thus, ODC expression in breast cancer cells is primarily regulated by tyrosine kinase- and protein kinase C-dependent pathways, whereas estrogens increase ODC activity through a novel type of synergistic interaction with growth factors that results in a decreased rate of enzyme turnover.
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PMID:Post-translational cooperativity of ornithine decarboxylase induction by estrogens and peptide growth factors in human breast cancer cells. 873 82

CD44s (standard form of CD44) is a transmembrane glycoprotein whose external domain displays extracellular matrix adhesion properties by binding both hyaluronic acid (HA) and collagen. The cytoplasmic domain of CD44s interacts with the cytoskeleton by binding directly to ankyrin. It has been shown that post-translational modifications, such as phosphorylation (by protein kinase C), acylation (by acyl-transferase) and GTP-binding enhanced CD44's interaction with cytoskeletal proteins. Most importantly, the interaction between CD44s and the cytoskeletal protein, ankyrin, is required for the modulation of CD44s cell surface expression and its adhesion function. Recently, a number of tumor cells and tissues have been shown to express CD44 variant (CD44v) isoforms. Using RT-PCR and DNA sequence analyses, we have found that unique CD44 splice variant isoforms are expressed in both prostate and breast cancer cell lines and carcinomas. Most importantly intracellular ankyrin is preferentially accumulated underneath the patched/capped structures of CD44 variant isoform in both breast and prostate cancer cells attached to HA-coated plates. We propose that selective expression of CD44v isoforms unique for certain metastatic carcinomas and their interaction with the cytoskeleton may play a pivotal role in regulating tumor cell behavior during tumor development and metastasis.
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PMID:Involvement of CD44 and its variant isoforms in membrane-cytoskeleton interaction, cell adhesion and tumor metastasis. 875 Jan 86

Cyclin D1 is frequently amplified and/or overexpressed in human breast cancer and several other types of cancer. To examine the role of cyclin D1 in normal mammary epithelial cells, in the present study we have overexpressed human cyclin D1 in the mouse mammary epithelial cell line HC11, using retrovirus-mediated transduction. We found that the cyclin D1 overexpresser clones displayed a decrease in saturation density, a decrease in anchorage-independent growth, an increased fraction of cells in the G(zero)-G1 phase, and increased expression of beta-casein, when compared to the control cells. The latter finding suggested that they were more differentiated. Furthermore, the cyclin D1 overexpressers displayed a marked increase in susceptibility to induction of apoptosis by serum withdrawal or by treatment with hydroxyurea or the protein kinase C inhibitors CGP 41251 and Ro31-8220. Thus, in some mammary epithelial cells, increased expression of cyclin D1 can inhibit growth, induce differentiation, and enhance apoptosis. These effects might be due, at least in part, to the fact that these derivatives displayed increased expression of the p27kip1 inhibitory protein.
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PMID:Increased expression of cyclin D1 in a murine mammary epithelial cell line induces p27kip1, inhibits growth, and enhances apoptosis. 878 Aug 83

Prostaglandin E2 (PGE2) levels are elevated in malignant human breast tissue. However, the cellular mechanisms regulating this arachidonate metabolism and the autocrine influence PGE2 production may have on breast cancer cell growth and function are unclear. In the present study, we have investigated the effects of 2 putative cyclo-oxygenase inducers, interleukin-1beta (IL-1beta) and the protein kinase C agonist 12-O-tetradecanoyl-phorbol-13-acetate (TPA), on PGE2 production, growth and aromatase activity in the MDA MB 231 breast cancer cell line. TPA stimulated a dose-dependent increase in PGE2 production, inhibited cell growth and stimulated aromatase activity. Although IL-1beta alone had no effect on any of these breast cancer cell functions, the cytokine greatly potentiated PGE2 production in the presence of TPA. Similarly, growth inhibition and aromatase stimulation in response to TPA were both further enhanced by IL-1beta treatment. Indomethacin and dexamethasone both prevented PGE2 production in response to IL-Ibeta and TPA but had no effect on the anti-proliferative action of the cytokine and phorbol ester. While indomethacin had no effect on induction of aromatase activity by IL-1beta and TPA, dexamethasone exhibited a temporally biphasic action. Dexamethasone alone stimulated aromatase activity and demonstrated a permissive action on aromatase stimulation by IL-1beta and TPA. However, pre-treatment of cells with dexamethasone prevented subsequent induction of aromatase activity by IL-1beta and TPA. Our study describes a novel synergistic interaction in response to protein kinase C activation and IL-1beta during the regulation of arachidonate metabolism, cell growth and aromatase activity in human breast cancer cells. We conclude that the cyclooxygenase pathway does not play a mediatory role during the inhibition of cell growth and the induction of aromatase activity by IL-1beta and TPA.
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PMID:Regulation of arachidonic acid metabolism, aromatase activity and growth in human breast cancer cells by interleukin-1beta and phorbol ester: dissociation of a mediatory role for prostaglandin E2 in the autocrine control of cell function. 878 59

We assessed the effect of the protein kinase C inhibitor 2,6-diamino-N-([1-(1-oxotridecyl)-2-piperidinyl]methyl)hexanami de (NPC 15437) on the action of anthracyclines, epipodophyllotoxins and vinca alkaloids in P-glycoprotein (Pgp)-expressing CH(R)C5 hamster ovary and MCF-7/Adria(R) human breast cancer cells. Flow microfluorimetry revealed that treatment of CH(R)C5 cells with 75 microM NPC 15437 for 1 h resulted in a 6- to 10-fold increase in the nuclear accumulation of daunorubicin. Colony forming assays revealed that treatment with 75 microM NPC 15437 was associated with a 4-fold decrease in the LD90 for etoposide and a 2.5-fold decrease in the LD50 for vincristine. At higher concentrations of NPC 15437, greater modulation of anthracycline accumulation was observed; but NPC 15437 itself inhibited subsequent colony formation. Similar effects on drug accumulation and cytotoxicity were observed in MCF-7/Adria(R) cells. Experiments designed to investigate the mechanism by which NPC 15437 exerts these effects revealed that treatment with the protein kinase C activator phorbol-12-myristate 12-acetate partially reversed the effect of NPC 15437, suggesting that NPC 15437 was exerting an effect through protein kinase C. Photoaffinity labeling experiments revealed that NPC 15437 also inhibited the binding of [3H]-azidopine to Pgp in isolated membrane vesicles. These results identify NPC 15437 [correction of NPC15437] as the prototype of a new class of potential Pgp modulators but indicate that the effects of this agent as a modulator are potentially limited by its cytotoxicity.
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PMID:Evaluation of 2,6-diamino-N-([1-(1-oxotridecyl)-2-piperidinyl]methyl)- hexanamide (NPC 15437), a protein kinase C inhibitor, as a modulator of P-glycoprotein-mediated resistance in vitro. 882 46

In human breast cancer cell lines, an inverse relationship exists between the basal levels of oestrogen receptor (ER) and epidermal growth factor receptor (EGF-R) gene expression. In addition, the tumour-promoting phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate (TPA) inhibits ER and stimulates EGF-R expression in MCF-7 breast cancer cells. This study aimed to define further the potential mechanisms involved in the modulation of ER and EGF-R gene expression by TPA. ER mRNA levels were reduced after 3 h and declined to 30% of control between 12 and 72 h after exposure to 10 nM TPA. This decrease in mRNA levels was preceded by an apparent fall in ER transcription rate. There was no effect on the stability of ER mRNA following pretreatment for 3-24 h with TPA, supporting the conclusion that the fall in ER mRNA levels was predominantly due to a decrease in ER transcription rate. Levels of EGF-R mRNA increased 10-fold by 12 h due predominantly to an increased transcription rate. The TPA-induced decrease in ER mRNA was unaffected by the simultaneous administration of the protein synthesis inhibitor cycloheximide, whereas the increase in EGF-R mRNA was inhibited by co-incubation with cycloheximide. These data indicate a requirement for continuing protein synthesis for the TPA effect on EGF-R but not on ER mRNA levels. Because the modulation of ER and EGF-R gene expression by TPA is likely to involve the protein kinase C (PKC) signal transduction pathway, the effects of other known activators of PKC were investigated. The non-phorboid tumour promoter mezerein modulated ER (an 80% decrease) and EGF-R (a 20-fold increase) mRNA levels in a similar manner to TPA. In contrast, neither 1,2-dioctanoyl-sn-glycerol (DiC8) nor 1-oleoyl-2-acetyl-sn-glycerol (OAG), both permeant analogues of the endogenous physiological activators of PKC, affected ER and EGF-R mRNA levels. These latter results were not due to a lack of efficacy because a single administration of DiC8 was as effective as TPA in inducing c-fos mRNA at 30 min. However DiC8 was less active in the later induction of c-myc mRNA. These data demonstrate reciprocal regulation of ER and EGF-R gene expression by TPA, involving effects on transcriptional events, which appear to be mediated by sustained activation of PKC.
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PMID:Inverse regulation of oestrogen receptor and epidermal growth factor receptor gene expression in MCF-7 breast cancer cells treated with phorbol ester. 883 62

To address the isoenzyme-specific involvement of protein kinase C (PKC) in breast cancer biology, hormone-responsive MCF-7 breast cancer cells were infected with either PKC-alpha or -beta 1 cDNAs subcloned in the retroviral expression vector pMV7. Several stable clones of PKC-overexpressing cells were generated. Western analysis revealed cross-regulation between the alpha and beta isoforms, because induction of overexpression of one up-regulated the other. Overexpression of the alpha and beta isoenzymes, on the other hand, did not affect the already high endogenous expression of the novel delta, epsilon, eta, and zeta isoforms. Compared with control clones, PKC-alpha- and -beta-overexpressing MCF-7 cells exhibited more drastic morphological changes in response to phorbol 12-myristate 13-acetate administration characterized by cellular flattening and vacuolization. More importantly, induction of PKC-alpha and -beta overexpression induced a less aggressive biological behavior, which was characterized by reduced in vitro invasiveness and markedly diminished tumor formation and growth in nude mice. These in vivo findings can probably best be explained by the dramatic down-regulation of estrogen receptor levels observed in tumors derived from PKC-alpha-infected MCF-7 cells. Our data clearly show that it is possible to induce a less aggressive breast cancer phenotype by altering PKC isoenzyme expression.
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PMID:Induction of a less aggressive breast cancer phenotype by protein kinase C-alpha and -beta overexpression. 887


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