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1.
Methods Mol Biol ; 2394: 3-18, 2022.
Article in English | MEDLINE | ID: mdl-35094318

ABSTRACT

We report a highly sensitive and selective CNT-switch liquid biopsy platform that detects and quantifies protein biomarker expressions from circulating tumor cells in blood for early detection of metastatic breast cancer and its relapse. This platform first isolates and enriches more than 99% of tumor cells with an off-chip micro-size membrane filtration technique and then conducts on-chip detection of the membrane and internal protein biomarkers of the tumor cells with high sensitivity and selectivity. High sensitivity is achieved with complete association of the antibody-antigen-antibody (Ab-Ag-Ab) complex by precisely and rapidly assembling carbon nanotubes (CNTs) across two parallel electrodes via sequential DC electrophoresis and dielectrophoresis (DEP) deposition. Each bridged CNT acts as a switch that connects the electrodes and closes the circuit to generate an electrical signal. The high selectivity is achieved with a critical hydrodynamic shear rate that irreversibly removes non-target linkers of the aligned CNTs. At present, we are able to detect the protein biomarkers from 5 spiked breast cancer tumor cells of different types within 7.5 ml of human blood samples. This demonstrates the potential of this platform as an inexpensive and noninvasive alternative to MRI scans and tissue biopsies currently used to detect early metastatic breast cancer and its relapse.


Subject(s)
Nanotubes, Carbon , Neoplastic Cells, Circulating , Biomarkers , Electrophoresis , Humans , Neoplasm Recurrence, Local
2.
Nat Commun ; 10(1): 2860, 2019 06 28.
Article in English | MEDLINE | ID: mdl-31253784

ABSTRACT

Lacking targetable molecular drivers, triple-negative breast cancer (TNBC) is the most clinically challenging subtype of breast cancer. In this study, we reveal that Death Effector Domain-containing DNA-binding protein (DEDD), which is overexpressed in > 60% of TNBCs, drives a mitogen-independent G1/S cell cycle transition through cytoplasm localization. The gain of cytosolic DEDD enhances cyclin D1 expression by interacting with heat shock 71 kDa protein 8 (HSC70). Concurrently, DEDD interacts with Rb family proteins and promotes their proteasome-mediated degradation. DEDD overexpression renders TNBCs vulnerable to cell cycle inhibition. Patients with TNBC have been excluded from CDK 4/6 inhibitor clinical trials due to the perceived high frequency of Rb-loss in TNBCs. Interestingly, our study demonstrated that, irrespective of Rb status, TNBCs with DEDD overexpression exhibit a DEDD-dependent vulnerability to combinatorial treatment with CDK4/6 inhibitor and EGFR inhibitor in vitro and in vivo. Thus, our study provided a rationale for the clinical application of CDK4/6 inhibitor combinatorial regimens for patients with TNBC.


Subject(s)
DNA-Binding Proteins/metabolism , Death Domain Receptor Signaling Adaptor Proteins/metabolism , Lapatinib/pharmacology , Triple Negative Breast Neoplasms/drug therapy , Antineoplastic Agents/pharmacology , Cell Cycle/drug effects , DNA-Binding Proteins/genetics , Death Domain Receptor Signaling Adaptor Proteins/genetics , ErbB Receptors/antagonists & inhibitors , Gene Expression Regulation, Neoplastic/drug effects , Humans , Receptor, ErbB-2/antagonists & inhibitors , Retinoblastoma Protein/genetics , Retinoblastoma Protein/metabolism , Triple Negative Breast Neoplasms/metabolism
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