Mechanisms of DDR1 in Reinforcing the Resistance to Radiotherapy in Breast Cancer Through the AMPK/SIRT1/PGC-1α Pathway.

Abstract

Breast cancer (BC) is the leading cause of cancer mortality in women. The emergence of resistance to radiotherapy (RT) is a great challenge for BC treatment. Discoidin domain receptor 1 (DDR1) can modulate the proliferation, migration, and apoptosis of cancer cells, but its role in RT of BC has not been illuminated. This project evaluated the expression of DDR1 in BC based on single-cell RNA sequencing data. We established RT-resistant strains through radiation and detected the expression of DDR1 using qPCR. The proliferation and apoptosis abilities of BC cells were evaluated using CCK-8, colony formation assay, and flow cytometry. Western blot and IHC were applied to detect the levels of proteins related to the AMPK/SIRT1/PGC-1α pathway. The effect of the DDR1-mediated pathway on resistance to RT in BC was explored in combination with an AMPK inhibitor. DDR1 was highly expressed in BC. In vitro experiments demonstrated that knocking down DDR1 repressed the viability of BC cells during RT, curbed cell proliferation, facilitated apoptosis, and elevated the levels of p-AMPK, SIRT1, and PGC-1α proteins. The addition of an AMPK inhibitor reversed the effects of DDR1 knockdown on cell proliferation and apoptosis. In vivo experiments showed that knocking down DDR1 inhibited tumor growth, and the inhibitory effect was stronger when combined with radiation therapy. This study revealed that the upregulation of DDR1 in BC may reinforce RT resistance by modulating the AMPK/SIRT1/PGC-1α pathway, thus providing a new therapeutic target for improving the sensitivity of BC to RT.