Abstract
Abstract Background: Zinc finger and BTB/POZ domain containing proteins (ZBTB) belong to a class of DNA-binding proteins that involved in development, differentiation and carcinogenesis. Our earlier findings showed that ZBTB2 expression was upregulated in cisplatin-resistant cells when compared with naïve cells. Increase in ZBTB2 expression was associated with ABCG2 drug transporter in drug resistance. However, the molecular mechanism of ZBTB2 in drug resistance and breast cancer metastasis remain largely unclear. Methods: A cisplatin-resistant triple-negative breast cancer (TNBC) cell line, MDA-MB-231/cis, was used to examine the involvement of drug transporter genes and the drug resistance pathway. Stem cell related genes were studied by RNA-sequencing. Characterization of ZBTB2 on cell proliferation, invasion and epithelial-mesenchymal transition (EMT) process were performed in ZBTB2 siRNA transfected cells. Stem-like cells properties were validated using aldehyde dehydrogenase (ALDH) activity, tumorsphere formation ability and stem cell markers. Metastatic animal model was used to study the genetic changes during metastasis and associated with the findings in clinical samples. Results: ZBTB2 has a higher expression in TNBC than other breast cancer subtypes. Also, the ZBTB2 expression is more prominent in primary breast tumor tissues when compared with non-tumor counterparts from TNBC patients. Silencing of ZBTB2 significantly reduced cell proliferation, invasion and sensitized cells to cisplatin through induction of apoptosis. Induction of ZBTB2 has been associated with breast cancer metastasis in mice model, where higher expression was seen in metastatic tumors when compared with primary tumors from tumor xenografts. ABCG2 and some epithelial-mesenchymal transition (EMT) markers (Twist 1, Snai2 and MMP-9) have been increased in metastatic tumors. Further, RNA sequencing analysis showed that ABCG2, IL6ST and FGFR1 were upregulated in MDA-MB-231/cis cells and downregulated in ZBTB2 siRNA transfected cells. Silencing of ZBTB2 reduced ALDH activity and tumorsphere formation ability. Treatment with inhibitor of NFkB (Bay11-7085) further decreased cell proliferation in cisplatin-resistant cells when compared with siZBTB2 alone. Expression of Stat3 and b-catenin were reduced upon knockdown of ZBTB2. Conclusion: Taken together, silencing of ZBTB2 sensitize cancer cells to cisplatin through regulation of EMT markers and stem-like cell properties in TNBC. These findings suggest a novel molecular pathway targeting ZBTB2/stat3/NFkB signaling to combat drug resistance in metastatic TNBC. Citation Format: Shin V, Siu MT, Cheuk I, Ho J, Chen J, Kwong A. ZBTB2 is a novel therapeutic target for cisplatin-resistance in metastatic breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-07-16.
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