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Title:
ErbB2/Her2-dependent downregulation of a cell death-promoting protein BLNK in breast cancer cells is required for 3D breast tumor growth | Cell Death & Disease
Description:
A significant proportion of breast cancers are driven by ErbB2/Her2 oncoprotein that they overexpress. These malignancies are typically treated with various ErbB2-targeted drugs, but many such cancers develop resistance to these agents and become incurable. Conceivably, treatment of ErbB2-positive cancers could be facilitated by use of agents blocking oncogenic signaling mechanisms downstream of ErbB2. However, current understanding of these mechanisms is limited. The ability of solid tumor cells to resist anoikis, cell death triggered by cell detachment from the extracellular matrix (ECM), is thought to be critical for 3D tumor growth. In an effort to understand the mechanisms of ErbB2-driven breast cancer cell anoikis resistance we found that detachment of non-malignant breast epithelial cells from the ECM upregulates a cell death-promoting tumor suppressor adapter protein BLNK and that ErbB2 blocks this upregulation by reducing tumor cell levels of transcription factor IRF6. We further observed that trastuzumab, a therapeutic anti-ErbB2 antibody, upregulates BLNK in human trastuzumab-sensitive but not trastuzumab-resistant ErbB2-positive breast cancer cells. Moreover, we established that BLNK promotes anoikis by activating p38 MAP kinase and that ErbB2-dependent BLNK downregulation blocks breast cancer cell anoikis. In search for pharmacological approaches allowing to upregulate BLNK in tumor cells we found that clinically approved proteasome inhibitor bortezomib upregulates IRF6 and BLNK in human breast cancer cells and inhibits their 3D growth in a BLNK-dependent manner. In addition, we found that BLNK upregulation in human ErbB2-positive breast cancer cells blocks their ability to form tumors in mice. Furthermore, we used publicly available data on mRNA levels in multiple breast cancers to demonstrate that increased BLNK mRNA levels correlate with increased relapse-free survival in a cohort of approximately 400 patients with ErbB2-positive breast cancer. In summary, we discovered a novel mechanism of ErbB2-driven 3D breast tumor growth mediated by ErbB2-dependent BLNK downregulation.
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cells, blnk, breast, cancer, cell, article, fig, detached, google, scholar, irf, anoikis, cas, erbb, ecm, expression, tumor, downregulation, control, found, epithelial, cultured, data, protein, erbbpositive, growth, mcfa, mcferbb, assayed, death, levels, medium, pmapk, nature, presence, blocks, factor, survival, bortezomib, usa, upregulation, increased, vector, annexin, doxycycline, western, published, treatment, mechanisms, observed,
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nature portfolio privacy policy pretrox-tetone™-puro expression vector bamhi-digested pretrox-tetone™-puro mcf-erbb2 cells mcf-erbb2-blnk nature annexin v-negative/7aad-positive cells pretrox-tetone™-puro- blnk vectors pretrox-tetone™-hygro-blnk vectors advertising erbb2/her2-positive breast carcinoma mitogen-activated protein kinase pbabe-hygro-irf6 expression vector sunnybrook research institute kaplan–meier analysis-based estimation annexin v-positive/7aad-negative annexin v-positive/7aad-positive irf6-overproducing mcf-erbb2 cells generate blnk-deficient cells social media control mcf-erbb2-vector cells erbb2-positive breast cancer pbabe-hygro expression vector reprints central proline-rich region erbb2-dependent erk activation pro-apoptotic protein perp erbb2/her2-dependent downregulation supplementary table 1 erbb2-dependent blnk downregulation breast development pbabe-irf6 expression vector medical research erbb2-induced blnk downregulation increased disease-free survival therapeutic anti-erbb2 antibody cell cycle-dependent manner pretrox-tetone™-puro c-terminal sh2 domain parental mcf-erbb2 cells health research pro-apoptotic protein bim pro-apoptotic proteins bax pretrox-tetone™-hygro erbb2-induced 3d growth original author nu/nu nude mice chromatin immunoprecipitation-sequencing analysis mcf-erbb2-blnk cells cells bt474t-blnk carrying
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headline:ErbB2/Her2-dependent downregulation of a cell death-promoting protein BLNK in breast cancer cells is required for 3D breast tumor growth
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headline:ErbB2/Her2-dependent downregulation of a cell death-promoting protein BLNK in breast cancer cells is required for 3D breast tumor growth
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