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 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.
Highlights
Breast cancer (BC) is the most common type of malignancy in the female population and represents the second leading cause of death in women among the cancer mortalities
We elucidate the signaling of chemoresistance in both cell lines and their Integrin subunit β1 (ITGB1)-knockdown mutants and elucidated mitogen-activated protein kinase (MAPK) pathway to be strongly upregulated upon Collagen type 1 (COL1) binding
We have recently reported that COL1 binding of human MCF-7 or MDA-MB-231 BC cells (BCCs) induces the upregulation of ABC efflux transporters, dominantly contributing to the development of a chemoresistance [23]
Summary
Breast cancer (BC) is the most common type of malignancy in the female population and represents the second leading cause of death in women among the cancer mortalities. BC is a heterogeneous disease with respect to the expression profile of molecular targets such as estrogen receptor, progesterone receptor, or human epidermal growth factor receptor 2 (HER2). While hormone-receptor-positive BC is mainly treated by anti-hormonal therapy, classical cytostatic drugs are still used against TNBC despite their side-effects. TNBC frequently express epidermal growth factor receptor (EGFR) at a varying extent, which has been considered as a potential biomarker for TNBC [3,4,5]. BC mortality is mainly caused by a chemoresistant recurrence of the disease after an initial successful treatment or by metastasis of BC.
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