Abstract:
:Invasive ductal carcinomas (IDC) of the breast are associated with altered expression of hormone receptors (HR), amplification or overexpression of HER2, or a triple-negative phenotype. The most aggressive cases of IDC are characterized by a high proliferation rate, a great propensity to metastasize, and their ability to resist to standard chemotherapy, hormone therapy, or HER2-targeted therapy. Using progression tissue microarrays, we here demonstrate that the serine/threonine kinase protein kinase D3 (PKD3) is highly upregulated in estrogen receptor (ER)-negative (ER(-)) tumors. We identify direct binding of the ER to the PRKD3 gene promoter as a mechanism of inhibition of PKD3 expression. Loss of ER results in upregulation of PKD3, leading to all hallmarks of aggressive IDC, including increased cell proliferation, migration, and invasion. This identifies ER(-) breast cancers as ideal for treatment with the PKD inhibitor CRT0066101. We show that similar to a knockdown of PKD3, treatment with this inhibitor targets all tumorigenic processes in vitro and decreases growth of primary tumors and metastasis in vivo. Our data strongly support the development of PKD inhibitors for clinical use for ER(-) breast cancers, including the triple-negative phenotype.
journal_name
Mol Cancer Therjournal_title
Molecular cancer therapeuticsauthors
Borges S,Perez EA,Thompson EA,Radisky DC,Geiger XJ,Storz Pdoi
10.1158/1535-7163.MCT-14-0945subject
Has Abstractpub_date
2015-06-01 00:00:00pages
1306-16issue
6eissn
1535-7163issn
1538-8514pii
1535-7163.MCT-14-0945journal_volume
14pub_type
杂志文章abstract::Mithramycin A is a DNA-binding antitumor agent, which has been clinically used in the therapies of several types of cancer and Paget's disease. In this study, we investigated the combined effect of mithramycin A and tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL) on apoptosis of cancer cells. In ...
journal_title:Molecular cancer therapeutics
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
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journal_title:Molecular cancer therapeutics
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pub_type: 杂志文章
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journal_title:Molecular cancer therapeutics
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pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-13-1090
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pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-17-0298
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doi:10.1158/1535-7163.MCT-17-0276
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