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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

Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53123 Bonn, Germany
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Int. J. Mol. Sci. 2020, 21(14), 4956; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21144956
Received: 12 June 2020 / Revised: 2 July 2020 / Accepted: 9 July 2020 / Published: 13 July 2020
(This article belongs to the Special Issue Breast Cancer: From Pathophysiology to Novel Therapeutic Approaches)
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 pharmacological interference. These findings provide evidence for the highly dynamic adaptation of breast cancer cells in maintaining matrix binding to circumvent cytotoxicity and highlight DDR1 signaling as a target for sensitization approaches. View Full-Text
Keywords: ABC transporter; breast cancer; chemoresistance; collagen; DDR1; EGFR; integrin; MAPK ABC transporter; breast cancer; chemoresistance; collagen; DDR1; EGFR; integrin; MAPK
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MDPI and ACS Style

Baltes, F.; Caspers, J.; Henze, S.; Schlesinger, M.; Bendas, G. 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. Int. J. Mol. Sci. 2020, 21, 4956. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21144956

AMA Style

Baltes F, Caspers J, Henze S, Schlesinger M, Bendas G. 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. 2020; 21(14):4956. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21144956

Chicago/Turabian Style

Baltes, Fabian, Julia Caspers, Svenja Henze, Martin Schlesinger, and Gerd Bendas. 2020. "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 21, no. 14: 4956. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21144956

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