The The Enzalutamide and EPI-001 Modulate Cell Proliferation and Metastasis Markers in T47D by Targeting AR/ARV7
Keywords:
Androgen receptor, Androgen receptor variant 7, metastasis, Epithelial to mesenchymal transition, breast cancer.
Abstract
Androgen receptor (AR) and its splicing variant 7 (ARv7) play vital roles in the pathobiology of breast cancer (BC) but their role in the estrogen receptor-positive (ER+) type is controversial. Hence, we studied the influence of the blockers of AR (Enzalutamide) and ARv7 (EPI-001) on tumorigenesis processes using T47D, an ER+ BC cell line. Several techniques were employed: Sulphorhodamine assay (SRB), Flow cytometry, Immunostaining, Scratch wound healing assay, Enzyme Linked Immunosorbent assay (ELISA), and Western blot. Mechanistically, the drugs successfully arrested the cell cycle at S-phase and downregulated the protein expression of cyclins A, E, & C. Additionally, they inhibited the cell proliferation stimulator nuclear factor kappa B (NF-ĸB), whereas only EPI-001 reduced the cell regulatory marker c-Myc. They also opposed the endothelial-to-mesenchymal transition (EMT) process, by boosting the epithelial marker E-cadherin and reducing the protein expression of the mesenchymal marker fibronectin. Their anti-metastatic potential was evidenced by the hindrance of cell migration using the wound healing assay and further confirmed by the downregulation of metalloproteinase (MMP) 2 and 9 protein expression, and protein content of Rho kinase (ROCK)1 and 2. Besides, by downregulating the protein expression of vascular endothelial growth factor (VEGF) the drugs point to their anti-angiogenic aptitude. In conclusion, this in-vitro study highlights the importance of targeting AR/ARv7 using Enzalutamide and EPI-001 in decreasing proliferation cell markers, EMT, and metastasis in ER+ BC cells, findings that may have great impact in the treatment of ER+ BC.
References
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Morales-Vasquez, F., Castillo-Sanchez, R., Gomora, M. J., Almaraz, M. A., Pedernera, E., Perez-Montiel, D., . . . Mendez, C. (2020). Expression of metalloproteinases MMP-2 and MMP-9 is associated to the presence of androgen receptor in epithelial ovarian tumors. J Ovarian Res, 13(1), 86. doi:10.1186/s13048-020-00676-x
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Brand, L. J., Olson, M. E., Ravindranathan, P., Guo, H., Kempema, A. M., Andrews, T. E., . . . Dehm, S. M. (2015). EPI-001 is a selective peroxisome proliferator-activated receptor-gamma modulator with inhibitory effects on androgen receptor expression and activity in prostate cancer. Oncotarget, 6(6), 3811-3824. doi:10.18632/oncotarget.2924
Caiazza, F., Murray, A., Madden, S. F., Synnott, N. C., Ryan, E. J., O'Donovan, N., . . . Duffy, M. J. (2016). Preclinical evaluation of the AR inhibitor enzalutamide in triple-negative BC cells. Endocr Relat Cancer, 23(4), 323-334. doi:10.1530/ERC-16-0068
Chua, H. L., Bhat-Nakshatri, P., Clare, S. E., Morimiya, A., Badve, S., & Nakshatri, H. (2007). NF-kappaB represses E-cadherin expression and enhances epithelial to mesenchymal transition of mammary epithelial cells: potential involvement of ZEB-1 and ZEB-2. Oncogene, 26(5), 711-724. doi:10.1038/sj.onc.1209808
Cochrane, D. R., Bernales, S., Jacobsen, B. M., Cittelly, D. M., Howe, E. N., D'Amato, N. C., . . . Richer, J. K. (2014). Role of the androgen receptor in BC and preclinical analysis of enzalutamide. BC Res, 16(1), R7. doi:10.1186/bcr3599
Das, D. K., Naidoo, M., Ilboudo, A., Park, J. Y., Ali, T., Krampis, K., . . . Ogunwobi, O. O. (2016). miR-1207-3p regulates the androgen receptor in prostate cancer via FNDC1/fibronectin. Exp Cell Res, 348(2), 190-200. doi:10.1016/j.yexcr.2016.09.021
Efthymiou, G., Saint, A., Ruff, M., Rekad, Z., Ciais, D., & Van Obberghen-Schilling, E. (2020). Shaping Up the Tumor Microenvironment With Cellular Fibronectin. Front Oncol, 10, 641. doi:10.3389/fonc.2020.00641
Ferguson, D. C., Mata, D. A., Tay, T. K., Traina, T. A., Gucalp, A., Chandarlapaty, S., . . . Ross, D. S. (2022). Androgen receptor splice variant-7 in BC: clinical and pathologic correlations. Mod Pathol, 35(3), 396-402. doi:10.1038/s41379-021-00924-5
Gerard, C., & Goldbeter, A. (2016). Dynamics of the mammalian cell cycle in physiological and pathological conditions. Wiley Interdiscip Rev Syst Biol Med, 8(2), 140-156. doi:10.1002/wsbm.1325
Gonzalez, L. O., Corte, M. D., Vazquez, J., Junquera, S., Sanchez, R., Alvarez, A. C., . . . Vizoso, F. J. (2008). Androgen receptor expresion in BC: relationship with clinicopathological characteristics of the tumors, prognosis, and expression of metalloproteases and their inhibitors. BMC Cancer, 8, 149. doi:10.1186/1471-2407-8-149
Hickey, T. E., Selth, L. A., Chia, K. M., Laven-Law, G., Milioli, H. H., Roden, D., . . . Tilley, W. D. (2021). The androgen receptor is a tumor suppressor in estrogen receptor-positive BC. Nat Med, 27(2), 310-320. doi:10.1038/s41591-020-01168-7
Holmes, A. G., Parker, J. B., Sagar, V., Truica, M. I., Soni, P. N., Han, H., . . . Chakravarti, D. (2022). A MYC inhibitor selectively alters the MYC and MAX cistromes and modulates the epigenomic landscape to regulate target gene expression. Sci Adv, 8(17), eabh3635. doi:10.1126/sciadv.abh3635
Hu, R., Dawood, S., Holmes, M. D., Collins, L. C., Schnitt, S. J., Cole, K., . . . Tamimi, R. M. (2011). Androgen receptor expression and BC survival in postmenopausal women. Clin Cancer Res, 17(7), 1867-1874. doi:10.1158/1078-0432.CCR-10-2021
Kroiss, A., Vincent, S., Decaussin-Petrucci, M., Meugnier, E., Viallet, J., Ruffion, A., . . . Allioli, N. (2015). Androgen-regulated microRNA-135a decreases prostate cancer cell migration and invasion through downregulating ROCK1 and ROCK2. Oncogene, 34(22), 2846-2855. doi:10.1038/onc.2014.222
Li, W., O'Shaughnessy, J., Hayes, D., Campone, M., Bondarenko, I., Zbarskaya, I., . . . Johnston, S. R. (2016). Biomarker Associations with Efficacy of Abiraterone Acetate and Exemestane in Postmenopausal Patients with Estrogen Receptor-Positive Metastatic BC. Clin Cancer Res, 22(24), 6002-6009. doi:10.1158/1078-0432.CCR-15-2452
Li, Y., Chan, S. C., Brand, L. J., Hwang, T. H., Silverstein, K. A., & Dehm, S. M. (2013). Androgen receptor splice variants mediate enzalutamide resistance in castration-resistant prostate cancer cell lines. Cancer Res, 73(2), 483-489. doi:10.1158/0008-5472.CAN-12-3630
Liao, R. S., Ma, S., Miao, L., Li, R., Yin, Y., & Raj, G. V. (2013). Androgen receptor-mediated non-genomic regulation of prostate cancer cell proliferation. Transl Androl Urol, 2(3), 187-196. doi:10.3978/j.issn.2223-4683.2013.09.07
Liu, J. Y., Chen, T. J., & Hwang, S. J. (2016). The Risk of BC in Women Using Menopausal Hormone Replacement Therapy in Taiwan. Int J Environ Res Public Health, 13(5). doi:10.3390/ijerph13050482
Liu, Y. N., Liu, Y., Lee, H. J., Hsu, Y. H., & Chen, J. H. (2008). Activated androgen receptor downregulates E-cadherin gene expression and promotes tumor metastasis. Mol Cell Biol, 28(23), 7096-7108. doi:10.1128/MCB.00449-08
Matsubara, M., & Bissell, M. J. (2016). Inhibitors of Rho kinase (ROCK) signaling revert the malignant phenotype of BC cells in 3D context. Oncotarget, 7(22), 31602-31622. doi:10.18632/oncotarget.9395
Montt-Guevara, M. M., Shortrede, J. E., Giretti, M. S., Giannini, A., Mannella, P., Russo, E., . . . Simoncini, T. (2016). Androgens Regulate T47D Cells Motility and Invasion through Actin Cytoskeleton Remodeling. Front Endocrinol (Lausanne), 7, 136. doi:10.3389/fendo.2016.00136
Morales-Vasquez, F., Castillo-Sanchez, R., Gomora, M. J., Almaraz, M. A., Pedernera, E., Perez-Montiel, D., . . . Mendez, C. (2020). Expression of metalloproteinases MMP-2 and MMP-9 is associated to the presence of androgen receptor in epithelial ovarian tumors. J Ovarian Res, 13(1), 86. doi:10.1186/s13048-020-00676-x
Najafi, M., Farhood, B., & Mortezaee, K. (2019). Extracellular matrix (ECM) stiffness and degradation as cancer drivers. J Cell Biochem, 120(3), 2782-2790. doi:10.1002/jcb.27681
Ni, M., Chen, Y., Fei, T., Li, D., Lim, E., Liu, X. S., & Brown, M. (2013). Amplitude modulation of androgen signaling by c-MYC. Genes Dev, 27(7), 734-748. doi:10.1101/gad.209569.112
Okamoto, T., Sanda, T., & Asamitsu, K. (2007). NF-kappa B signaling and carcinogenesis. Curr Pharm Des, 13(5), 447-462. doi:10.2174/138161207780162944
Pang, S. T., Flores-Morales, A., Skoog, L., Chuan, Y. C., Nordstedt, G., & Pousette, A. (2004). Regulation of matrix metalloproteinase 13 expression by androgen in prostate cancer. Oncol Rep, 11(6), 1187-1192.
Paolillo, M., & Schinelli, S. (2019). Extracellular Matrix Alterations in Metastatic Processes. Int J Mol Sci, 20(19). doi:10.3390/ijms20194947
Park, M. H., & Hong, J. T. (2016). Roles of NF-kappaB in Cancer and Inflammatory Diseases and Their Therapeutic Approaches. Cells, 5(2). doi:10.3390/cells5020015
Peters, A. A., Buchanan, G., Ricciardelli, C., Bianco-Miotto, T., Centenera, M. M., Harris, J. M., . . . Tilley, W. D. (2009). Androgen receptor inhibits estrogen receptor-alpha activity and is prognostic in BC. Cancer Res, 69(15), 6131-6140. doi:10.1158/0008-5472.CAN-09-0452
Quintero-Fabian, S., Arreola, R., Becerril-Villanueva, E., Torres-Romero, J. C., Arana-Argaez, V., Lara-Riegos, J., . . . Alvarez-Sanchez, M. E. (2019). Role of Matrix Metalloproteinases in Angiogenesis and Cancer. Front Oncol, 9, 1370. doi:10.3389/fonc.2019.01370
Scheau, C., Badarau, I. A., Costache, R., Caruntu, C., Mihai, G. L., Didilescu, A. C., . . . Neagu, M. (2019). The Role of Matrix Metalloproteinases in the Epithelial-Mesenchymal Transition of Hepatocellular Carcinoma. Anal Cell Pathol (Amst), 2019, 9423907. doi:10.1155/2019/9423907
Sharp, A., Coleman, I., Yuan, W., Sprenger, C., Dolling, D., Rodrigues, D. N., . . . Plymate, S. R. (2019). Androgen receptor splice variant-7 expression emerges with castration resistance in prostate cancer. J Clin Invest, 129(1), 192-208. doi:10.1172/JCI122819
Sherr, C. J., & Roberts, J. M. (2004). Living with or without cyclins and cyclin-dependent kinases. Genes Dev, 18(22), 2699-2711. doi:10.1101/gad.1256504
Sistigu, A., Di Modugno, F., Manic, G., & Nistico, P. (2017). Deciphering the loop of epithelial-mesenchymal transition, inflammatory cytokines and cancer immunoediting. Cytokine Growth Factor Rev, 36, 67-77. doi:10.1016/j.cytogfr.2017.05.008
Wang, B., Wu, S., Fang, Y., Sun, G., He, D., Hsieh, J. T., . . . Wu, K. (2020). The AKR1C3/AR-V7 complex maintains CRPC tumour growth by repressing B4GALT1 expression. J Cell Mol Med, 24(20), 12032-12043. doi:10.1111/jcmm.15831
Wang, Z., Banerjee, S., Li, Y., Rahman, K. M., Zhang, Y., & Sarkar, F. H. (2006). Down-regulation of notch-1 inhibits invasion by inactivation of nuclear factor-kappaB, vascular endothelial growth factor, and matrix metalloproteinase-9 in pancreatic cancer cells. Cancer Res, 66(5), 2778-2784. doi:10.1158/0008-5472.CAN-05-4281
Wenfei, J., Yaqin, S., Xin, W., Weiwei, H., Lin, T., Shengwang, T., . . . Xiaoxiang, G. (2019). Combined AR blockade overcomes the resistance of BC cells to palbociclib. Int J Biol Sci, 15(3), 522-532.
Woodward, W. A., Wachsberger, P., Burd, R., & Dicker, A. P. (2005). Effects of androgen suppression and radiation on prostate cancer suggest a role for angiogenesis blockade. Prostate Cancer Prostatic Dis, 8(2), 127-132. doi:10.1038/sj.pcan.4500779
Yeh, S., Hu, Y. C., Wang, P. H., Xie, C., Xu, Q., Tsai, M. Y., . . . Chang, C. (2003). Abnormal mammary gland development and growth retardation in female mice and MCF7 BC cells lacking androgen receptor. J Exp Med, 198(12), 1899-1908. doi:10.1084/jem.20031233
Yin, S., Cheryan, V. T., Xu, L., Rishi, A. K., & Reddy, K. B. (2017). Myc mediates cancer stem-like cells and EMT changes in triple negative BCs cells. PLoS One, 12(8), e0183578. doi:10.1371/journal.pone.0183578
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Published
2023-12-15
How to Cite
Ali , B. M., El-Abhar, H. S., Abdallah, D. M., Mohamed , G., Sharaky , M., Shouman , S. A., & Kamel, M. (2023). The The Enzalutamide and EPI-001 Modulate Cell Proliferation and Metastasis Markers in T47D by Targeting AR/ARV7. Indonesian Journal of Pharmacy, 34(4), 617-629. https://doi.org/10.22146/ijp.7416
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Section
Research Article
