The heparan sulfate proteoglycan Syndecan-1 modulates breast cancer radiation resistance in a CDK6-dependent manner2
Hypofractionated radiotherapy has shown beneficial effects in elderly breast cancer patients (1), whereas CDK4/6 inhibitors show promising therapeutic results as a second line therapy in postmenopausal breast cancer patients (2). Data from our laboratory link the proteoglycan Syndecan-1 both to irradiation resistance and cell proliferation (3). Here, we explore the molecular pathways linked to Syndecan-1-dependent radioresistance in breast cancer, as a prerequisite for improving postmenopausal radiotherapy.
A panel of human breast cancer cell lines was subjected to siRNA-mediated knockdown of Syndecan-1 or control siRNA-treatment. Cells were irradiated with a therapeutically relevant dose of 2-4Gy. Radiation resistance war studied by colony formation assay. Cell cycle progression was assessed by flow cytometry, and cell motility was monitored by video microscopy. DNA repair was studied by gammaH2X assay. Gene expression changes were analysed using Affymetrix array screening, qPCR, Western blotting and ELISA.
Syndecan-1 siRNA knockdown made MDA-MB-231, MDA-MB-468 and HCC1806 more resistant to irradiation. In MDA-MB-231 cells, Syndecan-1 depletion and irradiation had an additive effect on cell motility. All cell lines showed aberrant DNA repair and a slower progression through the cell cycle. Transcriptomic and qPCR analysis identified a downregulation of CREB1, ET-1 and CDK6 as molecular factors involved in the Syndecan-1 dependent phenotype.
Breast cancer cells are more resistant to irradiation when Syndecan-1 levels are substantially downregulated. The additive increase in cell motility of irradiated and Syndecan-1-depleted cells may indicate a functional role in irradiation-induced metastasis. In addition to a radioprotective upregulation of focal adhesion kinase activation, the slower CDK6-dependent progression through the cell cycle may result in an improved DNA repair in Syndecan-1-depleted cells.
(1) Doré M. Radiat Oncol. 2015;10:161.
(2) Huang HW. Medicine. 2019;98:e13909.
(3) Hassan H. FEBS J. 2013;280:2216-27.