Egr-1 Enhances Drug Resistance of Breast Cancer Cells by MDR1 Dependence
Keywords:
Egr-1;, Breast cancer;, MDR1;, Drug resistance.Abstract
Paclitaxel (PTX) is one of the most effective drugs used in the treatment of breast cancer. Nonetheless, the appearance of MDR1 (multidrug resistance 1) in tumor cells has become a significant hindrance for efficacious chemotherapy. In this study, we show that the expression level of Egr-1 (early growth response gene-1) in cancer tissues (from paclitaxel chemotherapy failure patients) and MCF-7/PTX cells (the breast cancer cell line that was resistant to paclitaxel) was increased. Cell proliferation assay and apoptosis assay revealed that Egr-1 could promote cell growth and inhibit apoptosis in MCF-7/PTX. Mechanistic studies indicated that Egr-1 could bind to the proximal MDR1 promoter and enhance MDR1 transcription. These findings indicate that paclitaxel induced Egr-1 accumulation and upregulated the expression of MDR1, thereby inducing the drug resistance in MCF-7/PTX. Our results suggest a novel pathway by which paclitaxel induces MDR1 expression, possibly illuminating a potential target pathway for the prevention of MDR1-mediated drug resistance.
Downloads
References
Bast RC Jr., Hennessy B, Mills GB. The biology of ovarian cancer: New opportunities for translation. Nat Rev Cancer. 2009;9(6):415-28.
Berry DA, Cronin KA, Plevritis SK, Fryback DG, Clarke L, Zelen M, et al. Effect of screening and adjuvant therapy on mortality from breast cancer. New Engl J Med. 2005;353(17):1784-92.
Bos JL. Linking Rap to cell adhesion. Curr Opin Cell Biol. 2005;17(2):123-8.
Chen J, Ren Q, Cai Y, Lin T, Zuo W, Wang J, et al. Mesenchymal stem cells drive paclitaxel resistance in ErbB2/ErbB3-coexpressing breast cancer cells via paracrine of neuregulin 1. Biochem Biophys Res Commun. 2018;501(1):212-9.
Chen JJ, Liu SP, Zhao J, Wang SC, Liu TJ, Li X. Effects of a novel photoactivated photosensitizer on MDR1 over-expressing human breast cancer cells. J Photochem Photobiol B Biol. 2017;171:67-74.
Christy BA, Lau LF, Nathans D. A gene activated in mouse 3T3 cells by serum growth factors encodes a protein with “zinc finger” sequences. Proc Natl Acad Sci USA. 1988;85(21):7857-61.
Crown J, O’Shaughnessy J, Gullo G. Emerging targeted therapies in triple-negative breast cancer. Ann Oncol. 2012;23(Suppl 6):vi56-65.
Dumitrescu RG, Cotarla I. Understanding breast cancer risk: Where do we stand in 2005? J Cell Mol Med. 2005;9(1):208-21.
Gottesman MM. Mechanisms of cancer drug resistance. Ann Rev Med. 2002;53:615-27.
Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: Role of ATP-dependent transporters. Nat Rev Cancer . 2002;2(1):48-58.
Guarneri V, Conte PF. The curability of breast cancer and the treatment of advanced disease. Eur J Nucl Med Mol Imaging. 2004;31(Suppl 1):S149-61.
Han W, Li L, Qiu S, Lu Q, Pan Q, Gu Y, et al. Shikonin circumvents cancer drug resistance by induction of a necroptotic death. Mol Cancer Ther. 2007;6(5):1641-9.
Huang RP, Fan Y, de Belle I, Niemeyer C, Gottardis MM, Mercola D, et al. Decreased Egr-1 expression in human, mouse and rat mammary cells and tissues correlates with tumor formation. Int J Cancer. 1997;72(1):102-9.
Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics. 2009. CA Cancer J Clin. 2009;59(4):225-49.
Jimenez-Cervantes C, Pichon B, Dumont JE, Maenhaut C. Activation by thyroid stimulating hormone of nerve growth factor-induced gene-B expression in thyrocytes in culture: relation with proliferation and specific gene expression. Biochim Biophys Acta. 1998;1403(3):232-44.
Kovalev AA, Tsvetaeva DA, Grudinskaja TV. Role of ABC-cassette transporters (MDR1, MRP1, BCRP) in the development of primary and acquired multiple drug resistance in patients with early and metastatic breast cancer. Exp Oncol. 2013;35(4):287-90.
Lemaire P, Revelant O, Bravo R, Charnay P. Two mouse genes encoding potential transcription factors with identical DNA-binding domains are activated by growth factors in cultured cells. Proc Natl Acad Sci USA . 1988;85(13):4691-5.
Mekhail TM, Markman M. Paclitaxel in cancer therapy. Exp Opin Pharmacother. 2002;3(6):755-66.
Milbrandt J. A nerve growth factor-induced gene encodes a possible transcriptional regulatory factor. Science. 1987;238(4828):797-9.
Morris PG, Fornier MN. Novel anti-tubulin cytotoxic agents for breast cancer. Exp Rev Anticancer Ther. 2009;9(2):175-85.
Pupo M, Pisano A, Lappano R, Santolla MF, De Francesco EM, Abonante S, et al. Bisphenol A induces gene expression changes and proliferative effects through GPER in breast cancer cells and cancer-associated fibroblasts. Environ Health Perspect. 2012;120(8):1177-82.
Roninson IB, Chin JE, Choi KG, Gros P, Housman DE, Fojo A, et al. Isolation of human mdr DNA sequences amplified in multidrug-resistant KB carcinoma cells. Proc Natl Acad Sci U S A. 1986;83(12):4538-42.
Ronski K, Sanders M, Burleson JA, Moyo V, Benn P, Fang M. Early growth response gene 1 (EGR1) is deleted in estrogen receptor-negative human breast carcinoma. Cancer. 2005;104(5):925-30.
Seidman AD, Tiersten A, Hudis C, Gollub M, Barrett S, Yao TJ, et al. Phase II trial of paclitaxel by 3-hour infusion as initial and salvage chemotherapy for metastatic breast cancer. J Clin Oncol. 1995;13(10):2575-81.
Sukhatme VP, Cao XM, Chang LC, Tsai-Morris CH, Stamenkovich D, Ferreira PC, et al. A zinc finger-encoding gene coregulated with c-fos during growth and differentiation, and after cellular depolarization. Cell. 1988;53(1):37-43.
Tao W, Shi JF, Zhang Q, Xue B, Sun YJ, Li CJ. Egr-1 enhances drug resistance of breast cancer by modulating MDR1 expression in a GGPPS-independent manner. Biomed Pharmacother 2013;67(3):197-202.
Vaidyanathan A, Sawers L, Gannon AL, Chakravarty P, Scott AL, Bray SE, et al. ABCB1 (MDR1) induction defines a common resistance mechanism in paclitaxel- and olaparib- resistant ovarian cancer cells. Br J Cancer. 2016;115(4):431-41.
Varnum BC, Lim RW, Kujubu DA, Luner SJ, Kaufman SE, Greenberger JS, et al. Granulocyte-macrophage colony-stimulating factor and tetradecanoyl phorbol acetate induce a distinct, restricted subset of primary-response TIS genes in both proliferating and terminally differentiated myeloid cells. Mol Cell Biol. 1989;9(8):3580-3.
Vivacqua A, Romeo E, De Marco P, De Francesco EM, Abonante S, Maggiolini M. GPER mediates the Egr-1 expression induced by 17beta-estradiol and 4-hydroxitamoxifen in breast and endometrial cancer cells. Breast Cancer Res Treat. 2012;133(3):1025-35.
Wang Y, Liu M, Zhang J, Liu Y, Kopp M, Zheng W, et al. Multidrug resistance protein 1 deficiency promotes doxorubicin-induced ovarian toxicity in female mice. Toxicol Sci. 2018b;163(1):279-92.
Wang YH, Imai Y, Shiseki M, Tanaka J, Motoji T. Knockdown of the Wnt receptor Frizzled-1 (FZD1) reduces MDR1/P-glycoprotein expression in multidrug resistant leukemic cells and inhibits leukemic cell proliferation. Leuk Res. 2018a;67:99-108.
Yamaguchi H, Chen CT, Chou CK, Pai A, Bornmann W, Hortobagyi GN, et al. Adenovirus 5 E1A enhances histone deacetylase inhibitors-induced apoptosis through Egr-1-mediated Bim upregulation. Oncogene. 2010;29(41):5619-29.
Zcharia E, Atzmon R, Nagler A, Shimoni A, Peretz T, Vlodavsky I, et al. Inhibition of matrix metalloproteinase-2 by halofuginone is mediated by the Egr1 transcription factor. Anticancer Drugs. 2012;23(10):1022-31.
Downloads
Published
Issue
Section
License
This work is licensed under a Creative Commons Attribution 4.0 International License.
All content of the journal, except where identified, is licensed under a Creative Commons attribution-type BY.
The on line journal has open and free access.
How to Cite
Funding data
-
Xuzhou Municipal Science and Technology Bureau
Grant numbers KC15SH075
