ABCB1 Regulates Immune Genes in Breast Cancer

Abstract

Background

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

Data Sharing Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Ethics Approval and Informed Consent

This study was approved by the Institutional Review Board of National Cheng Kung University Hospital (A-ER-106-157) and was performed according to the Declaration of Helsinki. Written informed consent was obtained from all participants. The animal study was approved by the National Laboratory Animal Center of National Applied Research Laboratories, Tainan, Taiwan (NLAC(TN)-104-M-028-R2/R3 & 107-M-001-R1/R2), and the Laboratory Animal Center, College of Medicine, National Cheng Kung University (NCKU-107226 and 108114).

Acknowledgments

The authors are thankful to the patient who participated in the study. We thank the Laboratory Animal Center, College of Medicine, National Cheng Kung University, National Laboratory Animal Center, NARLabs, Taiwan, and Taiwan Animal Consortium for the technical support. We were blessed with support from the late superintendent, Professor Pin-wen Lin. We also thank Dr Po-Hsien Huang and Miss Ya-Li Hsiao for their support.

Disclosure

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Additional information

Funding

This study was supported by the Ministry of Science and Technology (MOST) of Taiwan (grant No. 109-2314-B-006-018-MY3 to H.P.H.), the National Cheng Kung University Hospital (grant Nos. NCKUH-10902031 & NCKUH-11002013 & NCKUH-11102007 to H.P.H.), and the Chi Mei Medical Center (grant No. CMNKCKU11004).