ABCB1 regulates myeloid-derived suppressor cells-related immune factors in breast cancer

Abstract

Abstract Purpose Resistance to standard chemotherapy is a critical problem for breast cancer patients. The ATP-binding cassette (ABC) superfamily transporters actively pump out drugs and play an important role in chemoresistance. ABCB1 (ABC subfamily B, member 1, also named as multidrug resistance protein 1, MDR1) and suppressive myeloid-derived suppressor cells (MDSCs) potentially involve in chemoresistance of breast cancer. The relationship between ABCB1 and MDSC is less studied. Methods Microarray or RNA sequencing data was obtained from The Cancer Genome Atlas Breast Invasive Carcinoma in Genomic Data Commons Data Portal (GDC TCGA-BRCA) and GEO database. Expression of ABCB1 and MDSC-related genes was compared. Patient-derived xenograft (PDX) from HER2-enriced breast cancer was established to investigate the association of ABCB1 and MDSC-related genes in breast cancer. Results Expression of ABCB1 was increased in doxorubicin-selected MCF-7/ADR cells. High expression of ABCB1 mRNA was correlated with lymph node metastasis and worse overall survival of breast cancer patients. ABCB1 was positively correlated with IL6, CSF1, CSF3, or PTGS2 and negatively correlated with VEGF. PDX model from HER2-enriched stage IIA breast cancer was established. Treatment with doxorubicin or paclitaxel suppressed growth of P2 tumors and expression of ABCB1. Expression of IL6, CSF1, CSF3, PTGS2 was suppressed by paclitaxel, but not by doxorubicin. Intrasplenic MDSCs, including CD11b+Ly6G+ and CD11b+Ly6C+ cells, were higher than intratumor MDSCs in PDX-carrying nude mice. Clinically, the patient developed cancer recurrence after adjuvant chemotherapy with doxorubicin-based regimen and was well-controlled after paclitaxel-trastuzumab combined therapy.Conclusions ABCB1 is a poor predictor of breast cancer patients. Regulation of MDSC-related immune factors by ABCB1 and immune response to chemotherapeutic agents also contributes to cancer recurrence and treatment effect. PDX model is suitable to test expression of targeting genes and potential interaction with immune cells.