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

The breast tumour distribution of epidermal growth factor receptor (EGFR) was studied in 193 patients with primary breast cancer by immunocytochemistry on frozen sections. EGFR was correlated (P = 0.0009) with growth fraction assessed by Ki-67, and negatively correlated with oestrogen receptor (ER, P = 0.0001) and progesterone receptor (PR, P = 0.0001) status. In 47 patients, in-situ hybridisation for EGFR mRNA showed good agreement with the immunocytochemically assessed EGFR protein. There were, however, several tumours in which EGFR mRNA could be detected in the absence of EGFR protein and there were differences between the ER and PR status of those tumours in which translation of EGFR mRNA was not seen. The cause of these differences is unclear, but these findings may represent a clue as to the differential control of breast cancer cell receptors.
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PMID:Immunocytochemistry and in situ hybridisation of epidermal growth factor receptor and relation to prognostic factors in breast cancer. 132 Sep 9

To elucidate the relationship between epidermal growth factor (EGF)/transforming growth factor (TGF-alpha) and estradiol-17 beta (E) in cell proliferation, we examined their effects on the breast cancer cell line, CAMA-1. While E was able to consistently induce cell proliferation under a variety of experimental conditions, EGF/TGF-alpha was without effect. Despite the presence of the receptor (EGFR) gene, mature EGFR protein and mRNA were not detected by radioreceptor assay, 35S Met-labelling, and the Intron Differential RNA/PCR method under conditions in which cells remain responsive to E. Furthermore, TGF-alpha is not an autocrine factor in CAMA-1 cells. We demonstrated unequivocally that EGF/TGF-alpha interaction with EGFR is not an obligatory event in mediating estrogen-stimulated cell proliferation.
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PMID:Evidence of an EGF/TGE-alpha--independent pathway for estrogen-regulated cell proliferation. 191 78

In breast cancer, epidermal growth factor (EGF) receptor (EGFR) expression is inversely correlated with expression of estrogen receptor (ER) and predicts the prognosis and failure of endocrine therapy. We report here, for the first time, that in ER-positive breast cancer cell lines, MCF-7, T47D, and BT474, 17 beta-estradiol (E2) transiently induced EGFR messenger RNA (mRNA) levels 2- to 3-fold; this induction was prevented by the presence of the antiestrogen ICI 164,384 and was also reflected in the level of EGFR protein. Up-regulation of EGFR mRNA is most likely due to a direct effect of ER on the EGFR gene, with no involvement of protein synthesis, as it was not inhibited in the presence of cycloheximide; however, the subsequent down-regulation of EGFR required de novo protein synthesis. E2 had no effect on EGFR mRNA stability, and EGFR transcript levels were found to parallel EGFR mRNA levels, further supporting a direct transcriptional mechanism in the regulation of EGFR expression by estrogens. Additionally, sequencing of the EGFR promoter revealed putative imperfect estrogen-responsive elements that were capable of binding human ER. The transient nature of EGFR induction by E2, with a rapid return to a basal level that is dependent on protein synthesis, suggests that breast cancer cells possess active mechanisms to maintain low levels of EGFR expression in the presence of estrogen and a functional ER.
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PMID:Bimodal regulation of epidermal growth factor receptor by estrogen in breast cancer cells. 877 Aug 93

The cultivation of cells from primary breast cancers is very unpredictable. The majority of breast-cancer-derived cell lines are of metastatic origin. To define the characteristics of tumor cells which govern their ability to grow in vitro as primary cultures as well as continuous or established culture cell lineages, human mammary epithelial cancer (HMEC) cells from 18 cases of unselected primary breast cancer were propagated in culture. Propagation of HMEC cells in vitro as monolayers in primary culture was successful in 10 out of 18 (55.5%) cases, which showed continous proliferation of tumor cells only up to 6-8 passages before they reached senescence. An investigation of the effects of phenotypic expression of estrogen receptors (ER), the progesterone receptors, c-erbB-2 oncoprotein and epidermal growth factor receptors (EGFR) on the capacity of HMEC cells to grow in vitro as monolayers showed that expression of ER and EGFR is required for controlling tumor proliferative activity in vitro. Expression of ER protein made the growth of HMEC cells more difficult, while expression of EGFR protein made their growth in vitro easier. Phenotypic characteristics of floating HMEC cells were found to be different from those grown on cover slips as adherent cultures, suggesting a selective growth of HMEC cells of a specific phenotype in culture. Cultured HMEC cells in subsequent passages showed a decrease in their proliferative capacity, alterations in phenotypic characteristics and development of morphologic features of terminal differentiation, resulting in senescence.
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PMID:Role of steroid hormone and growth factor receptors and proto-oncogenes in the behavior of human mammary epithelial cancer cells in vitro. 925 31

Overexpression of the epidermal growth factor receptor (EGFR) has been observed in human breast tumors and is associated with poor prognosis in breast cancer patients. This would suggest that blocking the activity of the EGFR is a logical approach in the treatment of breast cancer. Three 20-mer phosphorothioate oligodeoxynucleotides were designed to target different regions of the human epidermal growth factor receptor (EGFR) mRNA. Several analogs of these oligodeoxynucleotides (the 2'-fluoro analog, the 2'-propoxy analog, and/or the 5-methyl cytosine analog) were also evaluated. We added these compounds to a human ovarian carcinoma cell line (SKOV3) and a human lung carcinoma line (A549), both of which overexpress the EGFR. All of these antisense oligonucleotides inhibited expression of the 10 kb EGFR mRNA (range: 22-97% inhibition) compared to a scrambled control oligonucleotide or an untreated control. Expression of the less prominent 5.6 kb EGFR mRNA band was also inhibited by all but two of the parent oligonucleotides. No inhibition of this 5.6 kb band was found with the control oligonucleotide. The reduction in the expression of EGFR mRNA by the three most potent antisense compounds was accompanied by a significant reduction of EGFR protein (90-98%) and in vitro growth inhibition of SKOV3 cells as compared to the control oligonucleotide.
Breast Cancer Res Treat 1999 Jan
PMID:Antisense oligonucleotides to the epidermal growth factor receptor. 1020 71

The expression of epidermal growth factor receptor (EGFR) mRNA and protein has been determined in a group of breast carcinomas and compared to oestrogen and progesterone receptor (ER, PgR) status, as well as pathological features. In situ hybridization using a digoxigenin-labelled oligonucleotide probe was applied to formalin-fixed paraffin-embedded sections, and immunohistochemistry was used to determine EGFR protein. EGFR mRNA was detected in 66% of carcinomas with a third having labelling similar to normal breast tissue, 22% heterogeneous weak to strong labelling, and 11% strong labelling. EGFR protein was detected in 36% and these tumours had a strong correlation to lack of ER and high histological grade. The presence of EGFR protein was strongly correlated with more intense labelling for EGFR mRNA (p < 0.0001). This contrasted with normal breast in which both EGFR protein and mRNA were present with varying degrees in both tumours and a normal breast control. The ER-/PgR- carcinomas showed the full range of EGFR mRNA labelling. It is postulated that oestrogen or oestrogen regulated proteins are involved in regulation of EGFR mRNA and protein. In a proportion of tumours lacking steroid receptors regulation is lost, leading to EGFR overexpression.
Breast Cancer Res Treat 1999 Jan
PMID:Expression of epidermal growth factor receptor mRNA and protein in primary breast carcinomas. 1032 94

We have examined the relative levels of oestrogen receptor beta (ERbeta) mRNA in 94 breast cancer specimens using a semi-quantitative RT-PCR procedure. We correlated its expression with ERalpha and various clinical, pathological and biochemical features of the disease. The level of ERbeta mRNA expression in these samples was found to be much lower than ERalpha. Although ERalpha mRNA species were found to be most frequently associated with histological grade I and II tumours, displaying tubular differentiation, low grades of nuclear pleomorphism and low mitotic activity, such features were not characteristic of ERbeta positive samples. Indeed, application of the Spearman rank correlation test revealed that there was an inverse association between ERbeta normalised levels and ERalpha protein HScore. Also ERbeta mRNA positive cancers were more frequently EGFR protein positive than their negative counterparts (p = 0.016), a feature normally associated with endocrine-insensitive disease. Our data suggest that although ERbeta levels are most likely lower than ERalpha, they may influence the biological behaviour of breast cancers containing low levels of ERalpha.
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PMID:A possible divergent role for the oestrogen receptor alpha and beta subtypes in clinical breast cancer. 1075 1

In our previous work Knoevenagel condensation of quinoline 2-, 3- and 4-carbaldehyde with malononitrile derivatives was used to produce a series of heteroarylidene malononitrile derivatives. Some of these heteroaromatic tyrphostins were potent inhibitors of the epidermal growth factor (EGF) receptor kinase. This work has now been extended by using 6-, 7-, and 8-quinolinecarbaldehyde to prepare 23 new quinoline-tyrphostins 1-23. Most of these compounds were moderately active against the MCF7 breast cancer cell line. The order of potency was 7- > 6 > 8-substituted quinoline, which indicates that increased activity of the 7-substituted quinolines is associated with electron deficiency at the 7-position in the quinoline ring. The most active compound, 12, formed from 7-quinolinecarbaldehyde and ethyl cyanoacetate, had an IC50 value of 2.3 microM. Compounds 1-23 showed similar IC50 values against the MCF7 and MCF7/ADR cell lines (the latter shows fourfold increased protein tyrosine kinase activity) except for the compounds 1 and 15 formed from 6-quinolinecarbaldehyde and malononitrile and 7-quinolinecarbaldehyde and cyanoacetamide, which showed a significant (11- and 42-fold, respectively) increase in potency against the MCF7/ADR cell line. Furthermore, no association was found between growth inhibition and inhibition of the EGFR protein tyrosine kinase (PTK), using a cell-free assay. In addition, new compounds were prepared from 2- and 4-quinolinecarbaldehyde with extended conjugation in the side chains (24-27) or with methoxypolyethoxyethyl esters in the side chain to increase water solubility (28 and 29). These compounds showed substantial cytotoxicity, with IC50 values in the range 1-25 microM, but similar values were observed against both cell lines. No association was found between inhibition of PTK and growth inhibition, again indicating that their mode of action may not be specific for the EGF receptor.
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PMID:Synthesis and antiproliferative activity of unsaturated quinoline derivatives. 1104 85

ErbB2 and cyclin D1 are interacting oncogenes that are particularly important in breast cancer. We demonstrated previously synergy between two drugs that separately address each oncogene, trastuzumab and flavopiridol. Here we examine the cellular basis for this interaction. Although both drugs are thought to alter cell cycle progression, the combination of trastuzumab and flavopiridol had little effect on G(1) progression or retinoblastoma protein phosphorylation. Instead, trastuzumab-flavopiridol synergistically enhanced apoptosis. Recent data have suggested that transcription elongation mediated by Cdk9 in P-TEFb is a more sensitive flavopiridol target than Cdk4. Supporting this view, we found synergy between 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole riboside and trastuzumab, but not between inhibitors of Cdk4 and trastuzumab. Similarly, a signature set of mRNAs that included the epidermal growth factor receptor (EGFR) responded to the combination of trastuzumab-flavopiridol in a gene expression array analysis. Three lines of evidence confirmed the EGFR is a potential target of flavopiridol-trastuzumab synergy: (a) EGFR protein expression was rapidly and completely lost after combination treatment; (b) a cell line that expresses amplified levels of both erbB2 and the EGFR was resistant to the combined drugs; and (c) treatment with epidermal growth factor prevented any therapeutic effects of flavopiridol and trastuzumab, singly or in combination. Taken together, our results suggest that synergy between flavopiridol and trastuzumab can result from enhanced apoptosis, and that combination effects on EGFR expression are involved in the interaction.
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PMID:Epidermal growth factor receptor expression is a candidate target of the synergistic combination of trastuzumab and flavopiridol in breast cancer. 1283 51

Previous studies have identified functional differences in non-involved breast tissue from cancer-containing breasts. This study has examined the expression of epidermal growth factor (EGFR) protein and mRNA in the non-involved breast of over 100 cancer-containing breasts and compared these with the same number of normal breast tissues from age-matched women with no history of breast cancer. Immunohistochemistry with EGFR1 antibody applied to frozen sections was used for the detection of protein, and in-situ hybridization using a digoxigenin-labelled oligonucleotide probe was the method for detecting mRNA. EGFR protein was detected in myoepithelial cells and to a lesser extent in epithelial cells, where it was predominantly basal or baso-lateral. There was a significant difference in the extent of staining in ducts and lobules between non-involved tissue from cancer-containing breasts and age-matched normal breasts, it being significantly greater in the latter (P<0.001). Labelling for EGFR mRNA was greater and more consistent in myoepithelial cells than epithelial cells overall. Differences were found for intensity of labeling, with it being significantly greater for normal breast tissue (P<0.001) than non-involved tissue from cancer-containing breasts. There is reduced EGFR expression in normal breast tissue from cancer-containing breasts when compared to age-matched breast tissue from women with no history of breast cancer. The mechanisms underlying this are unclear but in previous studies we have identified alterations in myoepithelial cells in cancer-containing breasts and the present findings may represent altered myoepithelial cell function.
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PMID:Altered expression of epidermal growth factor receptor in non-involved tissue of cancer-containing breasts. 1496 1


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