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

Although the growth of some estrogen receptor (ER) positive breast cancers can initially be hormonally manipulated, all will eventually escape hormonal control. It is possible that the expression of polypeptide growth factors is initially under the control of steroid hormones, while the hormone unresponsive state is characterized by constitutive expression of growth factors. We studied the relationship between hormone responsiveness and IGF expression in xenograft models. The ER+ T61 xenograft was established from a primary breast cancer and has been continually passaged in athymic mice. ER+ MCF-7 cells and ER-MDA-MB-231 cells were grown in tissue culture and then inoculated into athymic mice. ER+ xenograft growth was regulated by estrogen, but with opposite results--T61 xenografts are inhibited by estrogen, while MCF-7 xenografts require estrogen for tumor formation. All xenografts expressed type I and II IGF receptors. Although T61 xenografts also express an alternatively spliced IGF-I mRNA, its expression was not regulated by estrogen. Both xenografts expressed IGF-II in a hormonally regulated manner--T61 levels were depressed by estrogen, while MCF-7 levels were increased. Thus, in these model systems, xenograft regulation of tumor growth is accompanied by parallel changes in IGF-II expression. In the estrogen independent MDA-MB-231 cells, IGF-II was constitutively expressed. These data show that IGF-II expression correlates with estrogen treatment, suggesting that autocrine expression of IGF-II may mediate estrogen-regulated cell growth.
Breast Cancer Res Treat 1992
PMID:IGF-I and IGF-II expression in human breast cancer xenografts: relationship to hormone independence. 142 23

Experiments were undertaken to characterize mRNAs coding for the estrogen receptor (ER) in the human breast cancer cell line T47D. We report here the isolation of cDNAs corresponding to three isoforms of this receptor in addition to a majority of wild-type clones. Sequence analysis showed that these isoforms are generated through alternative splicing. None of the alternatively spliced isoforms of ER is able to bind to an estrogen-responsive element (ERE) in a gel mobility shift assay in vitro or to activate transcription of a reporter gene containing an ERE in vivo. One isoform, ER delta E3, which harbors a deletion of exon 3 encoding the second zinc finger of the DNA-binding domain, inhibits estrogen-dependent transcription activation in a dominant negative fashion when it is cotransfected with the wild-type ER and reporter plasmid. It also inhibits DNA binding of wild-type ER in a gel mobility shift assay in vitro. Since ER delta E3 is not able to bind to its response element, the observed inhibitory effect probably occurs through protein-protein interactions. This could involve the formation of a heterodimer between mutant and wild-type receptors, competition for a limiting transcription factor, or both. These results may have implications for understanding the loss of estrogen responsiveness that frequently occurs in breast cancer.
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PMID:Identification of a dominant negative form of the human estrogen receptor. 177 72

Coordinated expression of genes involved in development, differentiation and malignant transformation is regulated by transcription factors including homeodomain-containing proteins. However, most of their cDNA sequences are still unknown. We report here the molecular characterization of three newly cloned HOXA1 transcripts from human breast cancer cells. In addition, we provide evidence that these alternatively spliced transcripts encode one homeodomain-containing protein and two products lacking the conserved DNA-binding domain. Moreover, we demonstrate that all three HOXA1 transcripts are induced by retinoic acid in MCF7 cells. Taken together, our results suggest that HOXA1 gene may be a key element in the establishment of the breast cancer cell phenotype.
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PMID:Retinoic acid induces three newly cloned HOXA1 transcripts in MCF7 breast cancer cells. 748 13

Presence of alternatively spliced-estrogen receptor (ER) mRNA variants has been revealed in the breast cancer tissues. The ER variants transcribed from these mRNA variants were supposed to cause changes in the estrogen responsiveness of breast cancer. Although uterine endometrial cancer also has an estrogen-dependent profile, these ER mRNA variants have not yet been reported in the tumor. In the present study, we attempted to detect the exon 7 deletion- (del.7-) and exon 5 deletion (del.5) ER mRNA variants in normal human uterine endometrium (hEM) and uterine endometrial cancer tissue (hEC) by the use of reverse transcription-polymerase chain reaction-Southern blotting (RT-PCR-SB) with the PCR primers: hE4 (forward), hE6 (reverse), and hE8 (reverse), which were located in exons 4, 6, and 8, respectively. Two major products were generated from RNAs of both hEM and hEC with primers hE4 and hE8. The nucleotide sequence of the longer product was identical to exon 4-8 of human ER cDNA, whereas that of the shorter one completely deleted exon 7. Moreover, when the RT-PCR was done with the primers hE4 and hE6, the shorter product lacking exon 5 was detected with the longer one having the same sequence as exon 4-6 of human ER cDNA. Since the RT-PCR-SB with primers hE4 and hE8 produced a very low or undetectable level of the signals corresponding to del.5 ER mRNA variant, the level of del.7 ER mRNA variant seemed to be higher than that of del.5 ER mRNA variant.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Presence of alternatively spliced-estrogen receptor mRNA variants in normal human uterine endometrium and endometrial cancer. 754 77

CD44 is a transmembrane glycoprotein occurring in several isoforms with different extracellular regions. The various transcripts are encoded by one gene locus containing 20 exons, of which at least 10 can be alternatively spliced in nascent RNA. Isoforms encoded by the variant exons (termed CD44v) are highly restricted in their distribution in nonmalignant tissue as opposed to the standard form of CD44 (CD44s) abundant in many tissues. Specific variant isoforms containing exon 6v have been shown to render nonmetastatic rat tumor cells metastatic. Based on the prominent role in rat metastasis formation, CD44v isoforms were suggested to be involved in human tumor progression. Correlations between prognosis and expression of CD44v have been reported for gastric and colon carcinoma, for non-Hodgkin's lymphoma, and recently for breast carcinoma. We evaluated the expression of CD44 isoforms in node-positive (n = 119) and node-negative (n = 108) cases of breast carcinoma by immunohistochemistry using CD44v exon-specific mAbs. In a subset of 43 cases of high-risk patients, reverse transcription-PCR was used to determine the exon composition of the transcripts. Protein and RNA expression data were probed statistically for their correlation to survival of the patients and clinical risk factors. In contrast to recently published data (M. Kaufmann et al., Lancet, 345: 615-619, 1995), in our cohort disease-free and overall survival data did not indicate significant correlations with the expression of the analyzed isoforms in univariate and multivariate analyses. Comparison of CD44 protein expression with established clinical risk factors for survival such as tumor size (pT1+pT2) and histological grading revealed correlations with the presence of CD44s (P = 0.02 and P = 0.03, respectively) and CD44-9v (P = 0.05 for histological grading). Carcinoma tissues with elevated estrogen and progesterone receptor levels showed positive correlation with CD44-6v (P = 0.001), while a trend for significant coexpression of CD44s and CD44-9v isoforms was observed in estrogen receptor-positive tissues (P = 0.08 and 0.06, respectively). In breast cancer, CD44s, CD44-9v, and CD44-6v are apparently markers for cellular differentiation but not for tumor progression. Our data suggest that steroid hormone receptors may be associated with the in vivo expression of CD44-6v-containing isoforms in human mammary carcinoma.
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PMID:CD44 isoforms correlate with cellular differentiation but not with prognosis in human breast cancer. 758 12

The use of Schwann cell (SC) autotransplantation to influence neural repair in humans is dependent upon identifying mitogens that will effectively expand human Schwann cells (SCs) in culture. The recent purification and molecular cloning of glial growth factor (GGF), a potent mitogen for rat Schwann cells, has led to the recognition that a family of proteins (GGF/HRG/NDF/ARIA) are alternatively spliced products of a single gene. The heregulins (HRGs) have been characterized with respect to their influence on human breast cancer cell lines; here we examined whether the HRGs have mitogenic activity for human SCs. Using DNA synthesis assays and serial passaging of cells in culture, we demonstrate that HRG is an effective mitogen for human SCs and that, in the presence of agents that elevate cAMP, it is possible to expand these cells over multiple passages without overwhelming fibroblast contamination. One putative target for this family of proteins is p185erbB2, and EGF-like receptor tyrosine kinase that is encoded by the erbB2 protooncogene. In this report we also demonstrate that the erbB2/3/4 messages as well as the erbB2/3 receptor proteins are present within cultured human SCs. The addition of HRG to human SCs results in tyrosine phosphorylation of a 185 kDa protein. In the presence of stimulatory concentrations of HRG, a blocking monoclonal antibody (2C4) to p185erbB2 is capable of significantly inhibiting phosphorylation of a 185 kDa protein as well as the subsequent incorporation of 3H-thymidine within the human SC. These latter results implicate an important role for p185erbB2 in mediating the mitogenic response of human SCs to HRGs.
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PMID:The influence of heregulins on human Schwann cell proliferation. 786 1

Using polymerase chain reaction (PCR)-based methods, we have isolated cDNA clones of two new members of serine/threonine kinases, STK1 and STK2, from a cDNA library constructed from the BT-20 human breast cancer cell line. STK1 is transcribed as a 1.4 kilobase (kb) mRNA encoding for a protein of 346 amino acids. Based on amino acid sequence analysis, STK1 is 86% identical to the Xenopus p40mo15, a cdc2-related serine/threonine kinase recently found to be the activating kinase for p34cdc2 and p33cdk2. Thus, STK1 is most likely the human homologue of MO15. An alternatively spliced STK1 message expressed variably in cell lines and in primary carcinomas generates a predicted 58 amino acid protein that lacks the kinase domain. STK2 is transcribed into a 4.0 kb mRNA encoding for an 841 residue protein which exhibits 50% identity in the kinase domain with the mouse nek1 gene product, the relative of the fungal G2-M regulator, nimA. STK1 and STK2 display a variable pattern of expression among a series of primary carcinomas as well as cancer cell lines. Both STK1 and STK2 were expressed at the highest levels in the heart but were also detected in all other organs tested. In embryonal tissues, lower levels of expression were noted. Using cell cycle inhibitors, we have shown that both STK1 and STK2 mRNA levels remain relatively invariant through the cell cycle. Chromosomal assignment has localized STK1 on chromosome 2pcen-2p15, a region implicated in hereditary non-polyposis colorectal carcinoma, and STK2 on chromosome 3p21.1, a region frequently showing chromosomal alterations in renal cells carcinomas.
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PMID:Two novel human serine/threonine kinases with homologies to the cell cycle regulating Xenopus MO15, and NIMA kinases: cloning and characterization of their expression pattern. 820 44

We have used in vitro DNA binding assays as a measure of estrogen receptor (ER) function in human breast tumors. We found that the majority of ER+ (25 ER+/progesterone receptor [PgR]+, and 25 ER+/PgR-) tumors we examined were capable of binding consensus estrogen response element (ERE) oligonucleotides in this assay system. We found significant proteolytic activity in many of the tumors such that protease inhibitors were found to be essential during the preparation of tumor extracts. We next applied direct sequence analysis of the ER DNA binding domain of several of these tumors, and determined that the ER+/PgR- breast tumors did not contain mutations within the DNA binding domain which might explain their apparent discordant receptor phenotype. We did identify an alternatively spliced ER variant missing exon 3 of the DNA binding domain. This variant was unable to function as a transcriptional inducer of an estrogen-responsive reporter in a yeast assay system. Furthermore, the exon 3 ER deletion variant was expressed at equivalent levels in all of the ER+ breast tumors, so that it does not appear to be involved in the evolution of the ER+/PgR- breast cancer phenotype.
Breast Cancer Res Treat 1993
PMID:The ER-positive/PgR-negative breast cancer phenotype is not associated with mutations within the DNA binding domain. 821 56

Human meningiomas are rich in progesterone receptors (PR), which appear to be expressed autonomously. To investigate whether estrogen receptor (ER) variants which do not bind the ligand, but may constitutively induce PR expression, prevail in meningioma, we amplified cDNA by PCR in order to detect mRNA coding for the ER in meningioma which were ER-negative/PR-positive at the protein level. We screened for a portion of the ER which includes the DNA binding domain, the hinge region and the ligand binding domain. For this part of the ER we found a wild type mRNA in all 8 meningiomas tested. No mutations were detected. Apart from this transcript we found two alternatively spliced products missing exons 4 and 7, respectively in 8/8 meningioma specimens. These two products were not exclusive for meningioma, since they were also detected in the MCF7 breast cancer cell line which was used as control. ER deletion mutants missing exon 7 have already been reported [Ref. 1; Molec. Endocr. 5 (1991) 1571-1577]. These are dominant negative. To our knowledge, this is the first report on ER mutants missing exon 4. The presence of ER variants missing exon 4, which is probably not able to bind heat shock protein 90 and therefore may be constitutively active, might explain the autonomous expression of PR in meningioma.
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PMID:Wild type and alternatively spliced estrogen receptor messenger RNA in human meningioma tissue and MCF7 breast cancer cells. 849 31

Development of resistance to tamoxifen is a serious problem in treatment of breast cancer patients. Although the mechanisms for development of resistance are unclear, an altered expression of alternatively spliced estrogen receptor (ER) mRNA has been suggested to be involved. We have looked for differential expression of ER splice variants lacking exon 2 (ERdeltaE2), exon 3 (ERdeltaE3), exon 4 (ERdeltaE4), exon 5 (ERdeltaE5), exon 7 (ERdeltaE7), and exons 4 and 7 (ERdeltaE4, 7) in the human breast cancer cell line MCF-7 and 10 ER-positive MCF-7 sublines resistant to the antiestrogens tamoxifen, ICI 164,384 or ICI 182,780. No major differences in the expression were demonstrated between MCF-7 cells and resistant cells, indicating that ER splice variants are not involved in antiestrogen resistance in this model system. Furthermore, despite a high mRNA level of some of the ER splice variants, no corresponding proteins could be detected using Western blot analysis.
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PMID:Estrogen receptor messenger RNA splice variants are not involved in antiestrogen resistance in sublines of MCF-7 human breast cancer cells. 904 30


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