Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.5 (cathepsin D)
 4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In search of novel mechanisms leading to the development of antiestrogen-resistance in human breast tumors, we analyzed differences in the gene and protein expression pattern of the human breast carcinoma cell line T47D and its derivative T47D-r, which is resistant toward the pure antiestrogen ZM 182780 (Faslodex trade mark, fulvestrant). Affymetrix DNA chip hybridizations on the commercially available HuGeneFL and Hu95A arrays were carried out in parallel to the proteomics analysis where the total cellular protein content of T47D or T47D-r was separated on two-dimensional gels. Thirty-eight proteins were found to be reproducibly up- or down-regulated more than 2-fold in T47D-r versus T47D in the proteomics analysis. Comparison with differential mRNA analysis revealed that 19 of these were up- or down-regulated in parallel with the corresponding mRNA molecules, among which are the protease cathepsin D, the GTPases Rab11a and MxA, and the secreted protein hAG-2. For 11 proteins, the corresponding mRNA was not found to be differentially expressed, and for eight proteins an inverse regulation was found at the mRNA level. In summary, mRNA expression data, when combined with proteomic information, provide a more detailed picture of how breast cancer cells are altered in their antiestrogen-resistant compared with the antiestrogen-sensitive state.
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PMID:Comparison of proteomic and genomic analyses of the human breast cancer cell line T47D and the antiestrogen-resistant derivative T47D-r. 1455 97

Several breast cancer tumor models respond to estradiol (E(2)) by undergoing apoptosis, a phenomenon known to occur in clinical breast cancer. Before the application of tamoxifen as an endocrine therapy, high-dose E(2) or diethystilbesterol treatment was successfully used, albeit with unfavorable side effects. It is now recognized that such an approach may be a potential endocrine therapy option. We have explored the mechanism of E(2)-induced tumor regression in our T47D:A18/PKCalpha tumor model that exhibits autonomous growth, tamoxifen resistance, and E(2)-induced tumor regression. Fulvestrant, a selective estrogen receptor (ER) down-regulator, prevents T47D:A18/PKCalpha E(2)-induced tumor growth inhibition and regression when given before or after tumor establishment, respectively. Interestingly, E(2)-induced growth inhibition is only observed in vivo or when cells are grown in Matrigel but not in two-dimensional tissue culture, suggesting the requirement of the extracellular matrix. Tumor regression is accompanied by increased expression of the proapoptotic FasL/FasL ligand proteins and down-regulation of the prosurvival Akt pathway. Inhibition of colony formation in Matrigel by E(2) is accompanied by increased expression of FasL and short hairpin RNA knockdown partially reverses colony formation inhibition. Classic estrogen-responsive element-regulated transcription of pS2, PR, transforming growth factor-alpha, C3, and cathepsin D is independent of the inhibitory effects of E(2). A membrane-impermeable E(2)-BSA conjugate is capable of mediating growth inhibition, suggesting the involvement of a plasma membrane ER. We conclude that E(2)-induced T47D:A18/PKCalpha tumor regression requires participation of ER-alpha, the extracellular matrix, FasL/FasL ligand, and Akt pathways, allowing the opportunity to explore new predictive markers and therapeutic targets.
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PMID:Estradiol-induced regression in T47D:A18/PKCalpha tumors requires the estrogen receptor and interaction with the extracellular matrix. 1937 79

Premenopausal women are at highest risk for papillary and follicular thyroid carcinoma, implicating a role for estrogens in thyroid cancer. The expression of estrogen receptors alpha and beta (ER), the effects of estradiol (E2), selective estrogen receptor modulators (SERMs) 4-hydroxytamoxifen and raloxifene, and ER subtype selective agonists were examined in NPA87 and KAT5 papillary and WRO follicular thyroid carcinoma cell lines. All three thyroid cancer cell lines expressed full-length ERalpha and ERbeta proteins with cytoplasmic localization that was unaffected by E2. ICI 182,780 (Fulvestrant, an ER antagonist), and inhibitors of non-genomic E2-activated MAPK and PI3K signaling blocked E2-induced cell proliferation. SERMs acted in a cell line-specific manner. No E2-induced estrogen response element (ERE)-driven reporter activity was observed in transiently transfected thyroid cancer cells. However, E2 increased transcription of established endogenous E2-target genes, i.e., cathepsin D in WRO and cyclin D1 in both KAT5 and WRO cells in an ER-dependent manner as validated by inhibitor and siRNA experiments. In contrast, E2 did not increase progesterone receptor expression in the thyroid cancer cell lines. E2 stimulated phosphorylation of ERK1/2 in KAT5 and WRO cells and siERalpha or siERbeta inhibited E2-induced ERK phosphorylation. Expression of the putative membrane estrogen receptor GPR30 was detected in WRO, but not NPA87 or KAT5 cells. GPR30 expression was lower in WRO than MCF-7 human breast cancer cells. Overall, these findings suggest E2-mediated thyroid cancer cell proliferation involves ERalpha and ERbeta transcriptional and non-genomic signaling events.
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PMID:Estradiol-induced proliferation of papillary and follicular thyroid cancer cells is mediated by estrogen receptors alpha and beta. 2037 79