Decreased ABCG2 Expression in Prostate Cancer and Negatively Associated with Poorly Differentiated Grade and Biochemical Recurrence
AbstractSummary Few prognostic biomarkers have been identified for prostate cancer and there are clinical difficulties in distinguishing between relapsing and non-relapsing diseases. The aim of this study is to investigate the hypothesis that ABCG2 might be a potential biomarker for prostate cancer and could distinguish between aggressive tumours requiring radical intervention and those that have a good prognosis. ABCG2 is a transmembrane protein that plays a vital role in promoting proliferation and maintaining the undifferentiated phenotype of stem cells. It is thought to be a potential biomarker that can predict clinical progression and prognosis of different kinds of tumors. However, its role in prostate tumor remains unclear. Nuclear and cytoplasmic ABCG2 staining has been evaluated by immunohistochemistry using two sources of patient samples. The tissue microarray group consists of 96 cases including normal, adjacent normal and malignant prostate tissue samples. The Bath cohort consists of 30 samples, including samples from patients that had recurrent disease and those who remained disease-free. The immunohistochemical study showed nuclear and cytoplasmic ABCG2 expression in benign and malignant prostate samples. Cytoplasmic ABCG2 expression was also significantly reduced in prostate cancer compared to normal tissues. Cytoplasmic ABCG2 staining was negatively associated with increasing Gleason grade. In the Bath cohort, there was a negative association between ABCG2 expression and biochemical relapse. This preliminary data showed that ABCG2 might play a role in cancer formation and/or aggressiveness and warrants further investigation to understand its function and establish if it could be a potential diagnostic biomarker for prostate tumour.
Epstein, J.I. The Lower Urinary Tract and Male Genital System. In: S.L. Robbins, V. Kumar & R.S. Cotran, eds. Robbins and Cotran Pathologic Basis of Disease. 8th ed. USA: Saunders/Elsevier. 2010.
Prajapati, A., Gupta, S., Mistry, B. & Gupta, S. Prostate Stem Cells in the Development of Benign Prostate Hyperplasia and Prostate Cancer: Emerging Role and Concepts, 2013. BioMed Research International.
Signoretti, S. & Loda, M. Prostate stem cells: From development to cancer. Seminars in Cancer Biology, 2007, 17(3), pp. 219-224.
Goldstein, A.S., Huang, J., Guo, C., Garraway, I.P. & Witte, O.N. Identification of a cell of origin for human prostate cancer. Science (New York, N.Y.), 2010, 329(5991), p. 568.
Takao, T. & Tsujimura, A. Prostate stem cells: the niche and cell markers. International journal of urology: official journal of the Japanese Urological Association, 2008, 15(4), pp. 289-94.
Dunn, M.W. & Kazer, M.W. Prostate Cancer Overview. Seminars in Oncology Nursing, 2011, 27(4), pp. 241-250.
Qu, M., Ren, S.C. & Sun, Y.H. Current early diagnostic biomarkers of prostate cancer. Asian journal of andrology, 2014, 16(4), pp. 549-54.
Alghezi, D. Identifying potential new stem cell biomarkers for prostate cancer. Thesis (Ph.D.) - University of Bath, 2019.
Guzel, E., Karatas, O. F., Duz, M. B., Solak, M., Ittmann, M., & Ozen, M. Differential expression of stem cell markers and ABCG2 in recurrent prostate cancer. Prostate, 2014, 74(15), 1498-1505. https://doi.org/10.1002/pros.22867.
Ding, X. W., Wu, J. H., & Jiang, C. P. ABCG2: a potential marker of stem cells and novel target in stem cell and cancer therapy. Life Sci, 2010, 86(17-18), 631-637. https://doi.org/10.1016/j.lfs.2010.02.012.
Xiang, L., Su, P., Xia, S., Liu, Z., Wang, Y., Gao, P., & Zhou, G. (2011). ABCG2 is associated with HER-2 Expression, lymph node metastasis and clinical stage in breast invasive ductal carcinoma. Diagnostic Pathology, 6, 90-90. https://doi.org/10.1186/1746-1596-6-90.
Thompson, M., Lapointe, J., Choi, Y. L., Ong, D. E., Higgins, J. P., Brooks, J. D., & Pollack, J. R. Identification of candidate prostate cancer genes through comparative expression-profiling of seminal vesicle. Prostate, 2008, 68(11), 1248-1256. https://doi.org/10.1002/pros.20792.
Castellon, E. A., Valenzuela, R., Lillo, J., Castillo, V., Contreras, H. R., Gallegos, I., Mercado, A., & Huidobro, C. Molecular signature of cancer stem cells isolated from prostate carcinoma and expression of stem markers in different Gleason grades and metastasis. Biol Res, 2012, 45(3), 297-305. https://doi.org/10.4067/s0716-97602012000300011.
Hang, D., Dong, H.C., Ning, T., Dong, B., Hou, D.L. & Xu, W.G. Prognostic value of the stem cell markers CD133 and ABCG2 expression in esophageal squamous cell carcinoma. Diseases of the esophagus: official journal of the International Society for Diseases of the Esophagus, 2012, 25(7), pp. 638-44.
Pfeiffer, M. J., Smit, F. P., Sedelaar, J. P., & Schalken, J. A. Steroidogenic enzymes and stem cell markers are upregulated during androgen deprivation in prostate cancer. Mol Med, 2011, 17(7-8), 657-664. https://doi.org/10.2119/molmed.2010.00143.
Dalley, A.J., Pitty, L.P., Major, A.G., Abdulmajeed, A.A. & Farah, C.S. Expression of ABCG 2 and B mi‐ 1 in oral potentially malignant lesions and oral squamous cell carcinoma. Cancer Medicine, 2014, 3(2), pp. 273-283.
Vander Borght, S., Libbrecht, L., Katoonizadeh, A., van Pelt, J., Cassiman, D., Nevens, F., Van Lommel, A., Petersen, B. E., Fevery, J., Jansen, P. L., & Roskams, T. A. Breast cancer resistance protein (BCRP/ABCG2) is expressed by progenitor cells/reactive ductules and hepatocytes and its expression pattern is influenced by disease etiology and species type: possible functional consequences. J Histochem Cytochem, 2006, 54(9), 1051-1059. https://doi.org/10.1369/jhc.5A6912.2006.
Bhatia, P., Bernier, M., Sanghvi, M., Moaddel, R., Schwarting, R., Ramamoorthy, A., & Wainer, I. W. Breast cancer resistance protein (BCRP/ABCG2) localises to the nucleus in glioblastoma multiforme cells. Xenobiotica; the fate of foreign compounds in biological systems, 2012, 42(8), 748-755. https://doi.org/10.3109/00498254.2012.662726.
Liang, S.-C., Yang, C.-Y., Tseng, J.-Y., Wang, H.-L., Tung, C.-Y., Liu, H.-W., Chen, C.-Y., Yeh, Y.-C., Chou, T.-Y., Yang, M.-H., Whang-Peng, J., & Lin, C.-H. ABCG2 localizes to the nucleus and modulates CDH1 expression in lung cancer cells. Neoplasia, 2015, 17(3), 265-278. https://doi.org/10.1016/j.neo.2015.01.004.
Fetsch, P. A., Abati, A., Litman, T., Morisaki, K., Honjo, Y., Mittal, K., & Bates, S. E. Localization of the ABCG2 mitoxantrone resistance-associated protein in normal tissues. Cancer Lett, 2006, 235(1), 84-92. https://doi.org/10.1016/j.canlet.2005.04.024.
Gottesman, M. M., Fojo, T., & Bates, S. E. Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer, 2002, 2(1), 48-58. https://doi.org/10.1038/nrc706.
Nakanishi, T., & Ross, D. D. Breast cancer resistance protein (BCRP/ABCG2): its role in multidrug resistance and regulation of its gene expression. Chin J Cancer, 2012, 31(2), 73-99. https://doi.org/10.5732/cjc.011.10320.
Sabnis, N. G., Miller, A., Titus, M. A., & Huss, W. J. The Efflux Transporter ABCG2 Maintains Prostate Stem Cells. Mol Cancer Res, 2017, 15(2), 128-140. https://doi.org/10.1158/1541-7786.mcr-16-0270-t.
Gardner, E. R., Ahlers, C. M., Shukla, S., Sissung, T. M., Ockers, S. B., Price, D. K., Hamada, A., Robey, R. W., Steinberg, S. M., Ambudkar, S. V., Dahut, W. L., & Figg, W. D. Association of the ABCG2 C421A polymorphism with prostate cancer risk and survival. BJU Int, 2008, 102(11), 1694-1699. https://doi.org/10.1111/j.1464-410X.2008.07913.x.
Nariculam, J., Freeman, A., Bott, S., Munson, P., Cable, N., Brookman-Amissah, N., Williamson, M., Kirby, R. S., Masters, J., & Feneley, M. Utility of tissue microarrays for profiling prognostic biomarkers in clinically localized prostate cancer: the expression of BCL-2, E-cadherin, Ki-67 and p53 as predictors of biochemical failure after radical prostatectomy with nested control for clinical and pathological risk factors. Asian J Androl, 2009, 11(1), 109-118. https://doi.org/10.1038/aja.2008.22.
Rubin, M. A., Dunn, R., Strawderman, M., & Pienta, K. J. Tissue microarray sampling strategy for prostate cancer biomarker analysis. Am J Surg Pathol, 2002, 26(3), 312-319.
Symes, A. J., Eilertsen, M., Millar, M., Nariculam, J., Freeman, A., Notara, M., Feneley, M. R., Patel, H. R., Masters, J. R., & Ahmed, A. Quantitative analysis of BTF3, HINT1, NDRG1 and ODC1 protein over-expression in human prostate cancer tissue. PLoS ONE, 2013, 8(12), e84295. https://doi.org/10.1371/journal.pone.0084295.
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