Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04626 (erbB-2)
 5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The emergence of resistant cells reduces the efficacy of many forms of drug therapy in human breast cancer. In order to understand some of the possible mechanisms by which hormonally dependent human breast cancers develop resistance to progestin therapy we have developed a human breast cancer cell line (5-RP) which is resistant to the growth inhibitory effects of progestins in culture. These cells routinely grow in 10 microM medroxyprogesterone acetate (MPA). The cell line was developed from T-47D-5 human breast cancer cells by stepwise selection in increasing concentrations of MPA. The progestin-resistant phenotype was relatively stable as assessed by the removal of MPA from the medium for varying periods of time. 5-RP cells passaged in the absence of MPA were still essentially insensitive to the growth inhibitory effects of MPA for at least 22 passages. Even at 53 passages out of the drug the 5-RP line was still less sensitive than the original T-47D-5 parent line. Transforming growth factor-alpha (TGF-alpha) and epidermal growth factor (EGF) receptor mRNA were both increased in the 5-RP line compared to the T-47D-5. Consistent with increased TGF-alpha expression, the EGF receptor measured by ligand binding was decreased. When the cells were removed from MPA, TGF-alpha expression declined gradually, but EGF-receptor mRNA levels increased, as did EGF-binding activity. These cells remained estrogen and progesterone receptor positive. Although progestins did not downregulate estrogen receptor expression, they did downregulate progesterone receptor expression in the 5-RP line. The progesterone receptor level of the 5-RP line, in the absence of MPA, was approximately 58% of that found in T-47D-5 cells, even after MPA had been removed for long periods of time. This decrease in receptor level was reflected in decreased ability to respond to progestins as assessed by the decreased ability of MPA to activate expression of both an endogenous gene (EGF receptor) as well as a transiently transfected progestin-responsive gene (MMTV-TK-CAT). Progestin resistance in the 5-RP cell line appears to be multifactorial, involving both increased growth factor expression and decreased receptor levels. It is likely, however, that these two aspects do not account entirely for the progestin-resistant phenotype and as yet other unidentified mechanisms may also be involved.
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PMID:Mechanisms involved in the evolution of progestin resistance in human breast cancer cells. 184 41

The c-erbB-2 receptor tyrosine kinase proto-oncogene product is overexpressed in 20-30% of breast carcinomas and this has been shown to correlate with poor prognosis. Previous analysis of tumour-derived lines has demonstrated that although the c-erbB-2 gene is often amplified, overexpression can occur from a single-copy gene. Moreover, whether or not the gene is amplified, overexpressing cells produce 6- to 8-fold more mRNA per gene copy than low-expressing cells. In this paper, we examine the possible mechanisms causing this deregulation of c-erbB-2 mRNA accumulation. Nuclear run-on studies indicated that the extra mRNA accumulation was due to increased transcription of the gene in overexpressing cells. Promoter analyses using c-erbB-2 5' flanking sequences linked to CAT showed that the promoter is more active in overexpressing cells. Coupling promoter deletion functional studies with footprinting experiments, using nuclear extracts derived from both low and overexpressing cells, allowed the identification of a DNA-binding protein, OB2-1, which is considerably more abundant in a range of overexpressing lines. We discuss the possible role of OB2-1 in c-erbB-2 overexpression in breast tumour lines.
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PMID:A novel transcription factor, OB2-1, is required for overexpression of the proto-oncogene c-erbB-2 in mammary tumour lines. 809 45

The expression of the cellular gene coding for the epidermal growth factor (EGF) receptor (EGF-R) was assayed in the presence of hepatitis B virus (HBV) gene expression under different experimental conditions in human hepatoma-derived cells. First, transfection experiments of the well-differentiated HepG2 human hepatoma cell line using different expression vectors of the HBV X-region demonstrated that the X-gene product is capable of inducing EGF-R gene overexpression; in addition, by using a stable in vitro expression system for HBV, it was shown that EGF-R gene expression in these cells is greater than in the uninfected parent cells, and that this results in a three-fold increase in 125I-EGF binding. Finally, a CAT-expression assay was performed, indicating that regulatory regions of the EGF-R-gene are target sequences for X-protein trans-activation.
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PMID:Trans-activation of epidermal growth factor receptor gene by the hepatitis B virus X-gene product. 839 16

The erbB-2 receptor plays an important role in the prognosis of breast cancer. Amplification or overexpression of the erbB-2 proto-oncogene has been detected in 30% of breast cancers and is associated with poor patient prognosis. The significance of erbB-3 and erbB-4 in breast cancer is not yet known. The discovery of the growth factor heregulin (HRG) has allowed us to investigate a number of biological events that are regulated by erbB-2, -3, and -4 signal transduction. To determine the role of HRG in breast cancer tumor progression, we have developed an in vitro/in vivo model. We transfected HRG cDNA into the estrogen receptor (ER)-positive breast cancer cell line, MCF-7, and studied these cells as they progressed from a hormone-dependent to -independent phenotype. The biochemical and biological characteristics presented here demonstrate that overexpression of HRG induces morphological changes in MCF-7 cells as well as erbB-2, erbB-3, and erbB-4 autophosphorylation. MCF-7/ heregulin-transfected cells, which express relatively high levels of HRG, developed estrogen independence and resistance to antiestrogens in vitro and in vivo. This is consistent with a more aggressive hormone-independent phenotype. In contrast with control parental/wild-type cells, estradiol-mediated down-regulation of erbB-2 expression is blocked completely in this particular model system. These results indicate that HRG plays a role in the disruption of ER function. When a transient transfection with an ERE-CAT construct was introduced into these HRG-transfected MCF-7 cells, we observed that the ER was transcriptionally inactive. This suggests that ER signaling is altered in HRG-transfected cells. We observed that overexpression of HRG induces a more aggressive, hormone-independent phenotype that is most likely directly related to the constitutive activation of the erbB-2, erbB-3, and erbB-4 receptor signaling cascade. The data presented here suggest a close cross-regulation between the erbB-2/4 receptors and ER and provide new insights into the mechanism by which breast cancer cells acquire a hormone-independent phenotype.
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PMID:Involvement of heregulin-beta2 in the acquisition of the hormone-independent phenotype of breast cancer cells. 876 33