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

Nuclear steroid/thyroid/retinoid receptors and c-erbB membrane receptor tyrosine kinases control epithelial growth and differentiation. Retinoid receptors can dimerize with the vitamin D receptor, the glucocorticoid receptor or the thyroid receptor. Furthermore, multiple c-erbB receptor dimers have been identified. It has been shown that some of these receptor pathways communicate with each other via cross-connected regulatory networks. Molecular interactions between retinoid receptors or estrogen receptors (ER) and c-erbB-2, and between ER and retinoic acid receptor(RAR)-alpha have been reported. Here, we demonstrate the effects of steroids/thyroids/retinoids and of activators of protein kinase A (forskolin, Forsk) and C (12-O-tetradecanoylphorbol-13-acetate, TPA), on growth and expression of c-erbB and RARs in MCF-7 breast cancer cells, which contain high levels of RAR-alpha and -gamma, and which express significant amounts of c-erbB-2 and -3. All trans-retinoic acid (tRA), the anti-estrogen ICI 182 780 (ICI), Forsk and TPA reduced, whereas triiodothyronine and 17beta-estradiol (E2) stimulated cell growth. Flow cytometry revealed that tRA and E2 reduced c-erbB-2 and -3, whereas tamoxifen, Forsk and TPA up-regulated c-erbB-2. c-erbB-3 was co-regulated with c-erbB-2. Northern analysis demonstrated that RAR-alpha was down-regulated by dexamethasone, ICI, and TPA, whereas vitamin D3 and E2 up-regulated RAR-alpha. RAR-gamma expression was less responsive to such treatment, being reduced only by ICI and Forsk. These data indicate that nuclear receptor and protein kinase signaling communicate with each other and control the expression of RARs and c-erbB receptors. Efficient growth control requires the coordinated interplay of both receptor systems.
 ...
PMID:Involvement of nuclear steroid/thyroid/retinoid receptors and of protein kinases in the regulation of growth and of c-erbB and retinoic acid receptor expression in MCF-7 breast cancer cells. 1067 83

HER2/neu (erbB-2) overexpression has been causally associated with tamoxifen resistance in human breast cancer cells. Forced expression of HER2 in MCF-7 breast cancer cells resulted in mitogen-activated protein kinase (MAPK) hyperactivity and tamoxifen resistance. Inhibition of HER2 and MAPKs with AG1478 and U0126, respectively, as well as dominant-negative MEK-1/2 constructs restored the inhibitory effect of tamoxifen on estrogen receptor (ER)-mediated transcription and cell proliferation. Both AG1478 and U0126 also restored the tamoxifen-mediated association of ER with nuclear receptor corepressor (N-CoR) in the antiestrogen-resistant MCF-7 cells. Treatment with a combination of tamoxifen and a HER2 kinase inhibitor reduced tumor MAPK activity and markedly prevented growth of HER2-overexpressing MCF-7 xenografts in athymic mice. Thus, blockade of HER2 and MAPK signaling may enhance tamoxifen action and abrogate antiestrogen resistance in human breast cancer.
 ...
PMID:Inhibition of HER2/neu (erbB-2) and mitogen-activated protein kinases enhances tamoxifen action against HER2-overexpressing, tamoxifen-resistant breast cancer cells. 1105 87