Targeting Discoidin Domain Receptor 1 (DDR1) Signaling and Its Crosstalk with β1-integrin Emerges as a Key Factor for Breast Cancer Chemosensitization upon Collagen Type 1 Binding.

International Journal of Molecular Sciences
Fabian BaltesGerd Bendas

Abstract

Collagen type 1 (COL1) is a ubiquitously existing extracellular matrix protein whose high density in breast tissue favors metastasis and chemoresistance. COL1-binding of MDA-MB-231 and MCF-7 breast cancer cells is mainly dependent on β1-integrins (ITGB1). Here, we elucidate the signaling of chemoresistance in both cell lines and their ITGB1-knockdown mutants and elucidated MAPK pathway to be strongly upregulated upon COL1 binding. Notably, Discoidin Domain Receptor 1 (DDR1) was identified as another important COL1-sensor, which is permanently active but takes over the role of COL1-receptor maintaining MAPK activation in ITGB1-knockdown cells. Consequently, inhibition of DDR1 and ERK1/2 act synergistically, and sensitize the cells for cytostatic treatments using mitoxantrone, or doxorubicin, which was associated with an impaired ABCG2 drug efflux transporter activity. These data favor DDR1 as a promising target for cancer cell sensitization, most likely in combination with MAPK pathway inhibitors to circumvent COL1 induced transporter resistance axis. Since ITGB1-knockdown also induces upregulation of pEGFR in MDA-MB-231 cells, inhibitory approaches including EGFR inhibitors, such as gefitinib appear promising for pharmacologica...Continue Reading

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Citations

Dec 9, 2020·International Journal of Molecular Sciences·Kathleen Wantoch von RekowskiGerd Bendas
Feb 27, 2021·Clinical & Translational Oncology : Official Publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico·V MehtaA Munshi
Jul 3, 2021·International Journal of Molecular Sciences·Ahmed ElkamhawyKyeong Lee
Aug 31, 2021·Frontiers in Oncology·Tabatha Gutierrez PrietoVera Luiza Capelozzi

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Methods Mentioned

BETA
profiler
xenograft
PCR
flow cytometry
Protein Assay

Software Mentioned

[UNK]
Image Lab
CAM
GraphPad Prism
GraphPad
CompuSyn

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