Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P31749 (AKT)
 22,954 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A key step in the progression of breast cancer is the conversion of cells from an estrogen-dependent to an estrogen-independent state. Yet the molecular mechanisms underlying this transition in the control of cell proliferation of breast cancer cells remain poorly understood. A potential role for Ras-related GTPases in this process was suggested by the finding that BCAR3/AND-34, a protein isolated on the basis of its ability to convert MCF-7 and ZR-75 breast cancer cell lines to estrogen independence and tamoxifen resistance, is a guanine nucleotide exchange factor with the potential to activate the Ras-related Ral, R-Ras and Rap GTPases. In this study we investigated the potential contribution of these GTPases to the generation of estrogen-independence in MCF-7 cells. We found that elevated R-Ras but not Ral or Rap activity was sufficient to induce estrogen-independent proliferation of MCF-7 cells. The effect of R-Ras was dependent upon its ability to constitutively activate the AKT kinase. Interestingly, although AKT was also constitutively activated when estrogen-independent proliferation was induced by over-expression of EGF receptors, this mechanism of hormone independence did not require AKT activation. In contrast, EGF receptors did require Ral activation to induce estrogen-independent proliferation, while Ral activation was not required for estrogen-induced proliferation of MCF-7 cells. These findings suggest that Ral activity takes on a significant role in controlling cell proliferation of breast cancer cells when progression to estrogen-independence is associated with over-expression of EGF receptor family members. Moreover, because R-Ras promotes hormone-independent growth in a manner distinct from EGF receptors, it may participate in the conversion of breast cancer cells to estrogen independence when over-expression of EGF receptor family members is not involved.
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PMID:Involvement of R-Ras and Ral GTPases in estrogen-independent proliferation of breast cancer cells. 1238 18

Previously, we have identified a panel of breast cancer antiestrogen resistance (BCAR) genes. Several of these genes have clinical relevance because mRNA or protein levels associate with tamoxifen resistance or tumor aggressiveness. We postulated that changes in activation status of protein signaling networks induced by BCAR genes may provide better insight into the mechanisms underlying antiestrogen resistance. Key signal transduction pathways were analyzed for changes in activation or expression using reverse-phase protein microarrays probed with 78 antibodies against signaling proteins with known roles in tumorigenesis. We used ZR-75-1-derived cell lines transduced with AKT1, AKT2, BCAR1, BCAR3, BCAR4, EGFR, GRB7, HRAS, HRAS(v12) or HEF1 and MCF7-derived cell lines transduced with BCAR3, BCAR4 or EGFR. In the antiestrogen-resistant cell lines, we observed increased phosphorylation of several pathways involved in cell proliferation and survival. All tamoxifen-resistant cell lines contained high levels of phosphorylated AKT and its biochemically linked substrates Forkhead box O1/3. The activation of ERBB2, ERBB3 and the downstream modulators focal adhesion kinase and SHC were activated in cells with overexpression of BCAR4. Remarkable differences were observed for the levels of activated AMPK alpha1, cyclins, STAT5, STAT6, ERK1/2 and BCL2. The comparison of the cell signaling networks in estrogen-dependent and -independent cell lines revealed biochemically linked kinase-substrate markers that comprised systemically activated signaling pathways involved in tamoxifen resistance. Our results show that this model provides insights into the molecular and cellular mechanisms of breast cancer progression and antiestrogen resistance. This knowledge may help the development of novel targeted treatments.
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PMID:Protein pathway activation mapping reveals molecular networks associated with antiestrogen resistance in breast cancer cell lines. 2232 89