ABCB1 Regulates Immune Genes in Breast Cancer

Abstract

Han-Kun Chen,1 Yi-Ling Chen,2 Chih-Yang Wang,3,4 Wei-Pang Chung,5,6 Jung-Hua Fang,7 Ming-Derg Lai,8,9 Hui-Ping Hsu10 1Department of Surgery, Chi Mei Medical Center, Tainan, Taiwan; 2Department of Health and Nutrition, Chia Nan University of Pharmacy and Science, Tainan, Taiwan; 3PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; 4Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; 5Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 70403, Taiwan; 6Center of Applied Nanomedicine, National Cheng Kung University, Tainan, Taiwan; 7Laboratory Animal Center, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 8Department of Biochemistry and Molecular Biology, National Cheng Kung University, Tainan, Taiwan; 9Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 10Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, TaiwanCorrespondence: Hui-Ping Hsu, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan City, 704, Taiwan, Tel [phone], ext 5272, Fax [phone], Email [email protected]: 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 immune genes in breast cancer has not been widely studied.Methods: Microarray and RNA sequencing data were obtained from The Cancer Genome Atlas Breast Invasive Carcinoma in Genomic Data Commons Data Portal and Gene Expression Omnibus database. A patient-derived xenograft (PDX) model of HER2+ breast cancer was established to investigate the association between ABCB1 and immune genes in breast cancer.Results: Expression of ABCB1 increased in doxorubicin-selected MCF-7/ADR cells. High expression of ABCB1 mRNA is correlated with lymph-node metastasis and worse overall survival in patients with breast cancer. ABCB1 is positively correlated with IL6, CSF1, CSF3, and PTGS2. In the HER2+ stage IIA breast cancer PDX model, both doxorubicin and paclitaxel suppressed growth of P2 tumors. IL6, CSF1, CSF3, and PTGS2 expression were suppressed by paclitaxel but not doxorubicin. Intrasplenic MDSCs, including CD11b+Ly6G+ and CD11b+Ly6C+ cells, were more abundant 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.Conclusion: ABCB1 was a poor predictor of HER2+ LN– breast cancer. Regulation of immune genes by ABCB1 contributed to cancer recurrence and treatment effect. The PDX model was suitable for investigation the expression of target genes and expansion of immune cells.Keywords: breast cancer, ABC transporters, ABCB1, myeloid-derived suppressor cells, patient-derived xenograft

Keywords

• breast cancer
• abc transporters
• abcb1
• myeloid-derived suppressor cells
• patient-derived xenograft