ERβ as a Prognostic Factor for Colorectal Cancer Liver Metastasis

Zhenhua He, Xuelei Zhang, Sen Zhang, Zhenjie Wu, Jun Ouyang

Department of Colorectal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China..

DOI: 10.4236/jct.2012.326113                

Abstract

Estrogen plays an important role in the development of some cancers. However, previous studies on the influence of estrogen on colorectal cancer (CRC) have had conflicting conclusions, and there have been few reports on estrogens and liver metastasis. The aim of this study was to explore the prognostic impact of estrogens on CRC with liver metastasis. Eighty-six patients with CRC including 43 synchronous liver metastases were studied. Estrogen receptor β (ERβ) levels were assayed by immunohistochemistry in liver metastasis, CRC and adjacent normal tissues. Serum estrogen levels were measured by radioimmunoassay. The correlation between staining, clinicopathological parameters, and prognostic power were analyzed statistically. Significant differences were found in ERβ expression between liver metastasis (P = 0.012) and CRC (P = 0.002) compared to adjacent normal tissues. Serum estrogen levels in patients with liver metastases were significantly lower than those without liver metastasis (P = 0.012). The 1-, 2-, 3- and 5-year survival rates were 80%, 40%, 33% and 22%, respectively for the 43 patients with liver metastasis; and 94%, 63%, 49% and 49%, respectively for patients with positive ERβ in liver metastasis tissues, and 68%, 21%, 21% and 10%, respectively for those with negative ERβ (log-rank; P = 0.018). Cox regression test showed that ER beta (P = 0.029) were detected as the independent prognostic factors for liver metastasis of colorectal cancer. In conclusion, the present study suggests that ERβ may be a prognostic factor for synchronous liver metastasis of colorectal cancer.

Keywords

Estrogen Receptor β; Survival; Colorectal Cancer; Liver Metastasis

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	A. Jemal, F. Bray, M. M. Center, J. Ferlay, E. Ward and D. Forman, “Global Cancer Statistics,” CA: A Cancer Journal for Clinicians, Vol. 61, No. 2, 2011, pp. 69-90. doi:10.3322/caac.20107
[2]	D. Cunningham, W. Atkin, H. J. Lenz, H. T. Lynch, B. Minsky, B. Nordlinger and N. Starling, “Colorectal Cancer,” Lancet, Vol. 375, No. 9719, 2010, pp. 1030-1047. doi:10.1016/S0140-6736(10)60353-4
[3]	T. M. Pawlik and M. A. Choti, “Surgical Therapy for Colorectal Metastases to the Liver,” Journal of Gastrointestinal Surgery, Vol. 11, No. 8, 2007, pp. 1057-1077. doi:10.1007/s11605-006-0061-3
[4]	R. Lochan, S. A. White and D. M. Manas, “Liver Resection for Colorectal Liver Metastasis,” Surgical Oncology, Vol. 16, No. 1, 2007, pp. 33-45. doi:10.1016/j.suronc.2007.04.010
[5]	M. E. Barugel, C. Vargas and G. K. Waltier, “Metastatic Colorectal Cancer: Recent Advances in Its Clinical Management,” Expert Review of Anticancer Therapy, Vol. 9, No. 12, 2009, pp. 1829-1847. doi:10.1586/era.09.143
[6]	R. L. Nelson, T. Dollear, S. Freels and V. Persky, “The Relation of Age, Race, and Gender to the Subsite Location of Colorectal Carcinoma,” Cancer, Vol. 80, No. 2, 1997, pp. 193-197. doi:10.1002/(SICI)1097-0142(19970715)80:2<193::AID-CNCR4>3.0.CO;2-V
[7]	J. H. Koo, B. Jalaludin, S. K. Wong, A. Kneebone, S. J. Connor and R. W. Leong, “Improved Survival in Young Women with Colorectal Cancer,” The American Journal of Gastroenterology, Vol. 103, No. 6, 2008, pp. 1488-1495. doi:10.1111/j.1572-0241.2007.01779.x
[8]	F. Grodstein, P. A. Newcomb and M. J. Stampfer, “Post-menopausal Hormone Therapy and the Risk of Colorectal Cancer: A Review and Meta-Analysis,” American Journal of Medicine, Vol. 106, No. 5, 1999, pp. 574-582. doi:10.1016/S0002-9343(99)00063-7
[9]	H. D. Nelson, L. L. Humphrey, P. Nygren, S. M. Teutsch and J. D. Allan, “Postmenopausal Hormone Replacement Therapy: Scientific Review,” Journal of the American Medical Association, Vol. 288, No. 7, 2002, pp. 872-881. doi:10.1001/jama.288.7.872
[10]	G. Rennert, H. S. Rennert, M. Pinchev, O. Lavie and S. B. Gruber, “Use of Hormone Replacement Therapy and the Risk of Colorectal Cancer,” Journal of Clinical Oncology, Vol. 27, No. 27, 2009, pp. 4542-4547. doi:10.1200/JCO.2009.22.0764
[11]	S. Zhang, D. Wan, Z. Pan, Z. Zhou, G. Chen, Z. Lu, X. Wu and L. Li, “Multiple Factors Analysis on Liver Metastasis from Colorectal Cancer,” Zhonghua Zhong Liu Za Zhi, Vol. 24, No. 4, 2002, pp. 367-369.
[12]	G. G. Kuiper, E. Enmark, M. Pelto-Huikko, S. Nilsson and J. A. Gustafsson, “Cloning of a Novel Receptor Expressed in Rat Prostate and Ovary,” Proceedings of the National Academy of Sciences of the United States, Vol. 93, No. 12, 1996, pp. 5925-5930. doi:10.1073/pnas.93.12.5925
[13]	D. Elkind, “Cognitive Adaptation in Latency. The Construction of Social Reality,” Canadian Journal of Psychiatry, Vol. 21, No. 4, 1976, pp. 186-191.
[14]	K. M. Dobrzycka, S. M. Townson, S. Jiang and S. Oesterreich, “Estrogen Receptor Corepressors—A Role in Human Breast Cancer?” Endocrine-Related Cancer, Vol. 10, No. 4, 2003, pp. 517-536. doi:10.1677/erc.0.0100517
[15]	J. M. Hall, J. F. Couse and K. S. Korach, “The Multifaceted Mechanisms of Estradiol and Estrogen Receptor Signaling,” The Journal of Biological Chemistry, Vol. 276, No. 40, 2001, pp. 36869-36872. doi:10.1074/jbc.R100029200
[16]	D. Witte, M. Chirala, A. Younes, Y. Li and M. Younes, “Estrogen Receptor Beta Is Expressed in Human Colorectal Adenocarcinoma,” Human Pathology, Vol. 32, No. 9, 2001, pp. 940-944. doi:10.1053/hupa.2001.27117
[17]	P. A. Konstantinopoulos, A. Kominea, G. Vandoros, G. P. Sykiotis, P. Andricopoulos, I. Varakis, G. Sotiropoulou-Bonikou and A. G. Papavassiliou, “Oestrogen Receptor Beta (Erbeta) Is Abundantly Expressed in Normal Colonic Mucosa, but Declines in Colon Adenocarcinoma Paralleling the Tumour’s Dedifferentiation,” European Journal of Cancer, Vol. 39, No. 9, 2003, pp. 1251-1258. doi:10.1016/S0959-8049(03)00239-9
[18]	L. Q. Xie, J. P. Yu and H. S. Luo, “Expression of Estrogen Receptor Beta in Human Colorectal Cancer,” World Journal of Gastroenterology, Vol. 10, No. 2, 2004, pp. 214-217.
[19]	M. K. G. Leslie H. Sobin and C. Wittekind, “TNM Classification of Malignant Tumours,” 7th Edition, Wiley-Liss, New York, 2011.
[20]	H. Kawasaki, D. C. Altieri, C. D. Lu, M. Toyoda, T. Tenjo and N. Tanigawa, “Inhibition of Apoptosis by Survivin Predicts Shorter Survival Rates in Colorectal Cancer,” Cancer Research, Vol. 58, No. 22, 1998, pp. 5071-5074.
[21]	F. A. Sinicrope, S. B. Ruan, K. R. Cleary, L. C. Stephens, J. J. Lee and B. Levin, “bcl-2 and p53 Oncoprotein Expression during Colorectal Tumorigenesis,” Cancer Research, Vol. 55, No. 2, 1995, pp. 237-241.
[22]	R. L. Prentice, M. Pettinger, S. A. A. Beresford, J. Wactawski-Wende, F. A. Hubbell, M. L. Stefanick and R. T. Chlebowski, “Colorectal Cancer in Relation to Post-menopausal Estrogen and Estrogen plus Progestin in the Women’s Health Initiative Clinical Trial and Observational Study,” Cancer Epidemiology Biomarkers & Prevention, Vol. 18, No. 5, 2009, pp. 1531-1537. doi:10.1158/1055-9965.EPI-08-1209
[23]	J. E. Rossouw, G. L. Anderson, R. L. Prentice, A. Z. La-Croix, C. Kooperberg, M. L. Stefanick, R. D. Jackson, S. A. Beresford, B. V. Howard, K. C. Johnson, J. M. Kotchen and J. Ockene, “Risks and Benefits of Estrogen plus Progestin In Healthy Postmenopausal Women: Principal Results from the Women’s Health Initiative Randomized Controlled Trial,” Journal of the American Medical Association, Vol. 288, No. 3, 2002, pp. 321-333. doi:10.1001/jama.288.3.321
[24]	E. Fernandez, C. La Vecchia, A. Balducci, L. Chatenoud, S. Franceschi and E. Negri, “Oral Contraceptives and Colorectal Cancer Risk: A Meta-Analysis,” British Journal of Cancer, Vol. 84, No. 5, 2001, pp. 722-727. doi:10.1054/bjoc.2000.1622
[25]	R. T. Chlebowski, J. Wactawski-Wende, C. Ritenbaugh, F. A. Hubbell, J. Ascensao, R. J. Rodabough, C. A. Rosenberg, V. M. Taylor, R. Harris, C. Chen, L. L. Adams-Campbell and E. White, “Estrogen plus Progestin and Colorectal Cancer in Postmenopausal Women,” The New England Journal of Medicine, Vol. 350, No. 10, 2004, pp. 991-1004. doi:10.1056/NEJMoa032071
[26]	M. L. Slattery, C. Sweeney, M. Murtaugh, K. N. Ma, R. K. Wolff, J. D. Potter, B. J. Caan and W. Samowitz, “Associations between ERalpha, ERbeta, and AR Genotypes And Colon and Rectal Cancer,” Cancer Epidemiology, Biomarkers & Prevention, Vol. 14, No. 12, 2005, pp. 2936-2942. doi:10.1158/1055-9965.EPI-05-0514
[27]	M. Campbell-Thompson, I. J. Lynch and B. Bhardwaj, “Expression of Estrogen Receptor (ER) Subtypes and ERbeta Isoforms in Colon Cancer,” Cancer Research, Vol. 61, No. 2, 2001, pp. 632-640.
[28]	E. F. Foley, A. A. Jazaeri, M. A. Shupnik, O. Jazaeri and L. W. Rice, “Selective Loss of Estrogen Receptor Beta in Malignant Human Colon,” Cancer Research, Vol. 60, No. 2, 2000, pp. 245-248.
[29]	Y. J. Fang, Z. H. Lu, F. Wang, X. J. Wu, L. R. Li, L. Y. Zhang, Z. Z. Pan and D. S. Wan, “Prognostic Impact of ERbeta and MMP7 Expression on Overall Survival in Colon Cancer,” Tumor Biology, Vol. 31, No. 6, 2010, pp. 651-658. doi:10.1007/s13277-010-0082-0
[30]	H. G. Elbanna, M. A. Ebrahim, A. M. Abbas, K. Zalata and M. A. Hashim, “Potential Value of Estrogen Receptor Beta Expression in Colorectal Carcinoma: Interaction with Apoptotic Index,” Journal of Gastrointestinal Cancer, 2010.
[31]	P. D. Grivas, V. Tzelepi, G. Sotiropoulou-Bonikou, Z. Kefalopoulou, A. G. Papavassiliou and H. Kalofonos, “Estrogen Receptor Alpha/Beta, AIB1, and TIF2 in Colorectal Carcinogenesis: Do Coregulators Have Prognostic Significance?” International Journal of Colorectal Disease, Vol. 24, No. 6, 2009, pp. 613-622. doi:10.1007/s00384-009-0647-9
[32]	N. Jassam, S. M. Bell, V. Speirs and P. Quirke, “Loss of Expression of Oestrogen Receptor Beta in Colon Cancer and Its Association with Dukes’ Staging,” Oncology Reports, Vol. 14, No. 1, 2005, pp. 17-21.
[33]	J. W. Nash, C. Morrison and W. L. Frankel, “The Utility of Estrogen Receptor and Progesterone Receptor Immunohistochemistry in the Distinction of Metastatic Breast Carcinoma from Other Tumors in the Liver,” Archives of Pathology & Laboratory Medicine, Vol. 127, No. 12, 2003, pp. 1591-1595.
[34]	M. Iavarone, P. Lampertico, C. Seletti, M. Francesca Donato, G. Ronchi, E. del Ninno and M. Colombo, “The Clinical and Pathogenetic Significance of Estrogen Receptor-Beta Expression in Chronic Liver Diseases and Liver Carcinoma,” Cancer, Vol. 98, No. 3, 2003, pp. 529-534. doi:10.1002/cncr.11528
[35]	H. Sugiura, T. Toyama, Y. Hara, Z. Zhang, S. Kobayashi, Y. Fujii, H. Iwase and H. Yamashita, “Expression of Estrogen Receptor Beta Wild-Type and Its Variant ERbetacx/Beta2 Is Correlated with Better Prognosis in Breast Cancer,” Japanese Journal of Clinical Oncology, Vol. 37, No. 11, 2007, pp. 820-828. doi:10.1093/jjco/hym114
[36]	L. Nakopoulou, A. C. Lazaris, E. G. Panayotopoulou, I. Giannopoulou, N. Givalos, S. Markaki and A. Keramopoulos, “The Favourable Prognostic Value of Oestrogen Receptor Beta Immunohistochemical Expression in Breast Cancer,” Journal of Clinical Pathology, Vol. 57, No. 5, 2004, pp. 523-528. doi:10.1136/jcp.2003.008599
[37]	C. Y. Xu, J. L. Guo, Z. N. Jiang, S. D. Xie, J. G. Shen, J. Y. Shen and L. B. Wang, “Prognostic Role of Estrogen Receptor Alpha and Estrogen Receptor Beta in Gastric Cancer,” Annals of Surgical Oncology, Vol. 17, No. 9, 2010, pp. 2503-2509. doi:10.1245/s10434-010-1031-2
[38]	J. Cassidy, J. Tabernero, C. Twelves, R. Brunet, C. Butts, T. Conroy, F. Debraud, A. Figer, J. Grossmann, N. Sawada, P. Schoffski, A. Sobrero, E. Van Cutsem and E. Diaz-Rubio, “XELOX (Capecitabine plus Oxaliplatin): Active First-Line Therapy for Patients with Metastatic Colorectal Cancer,” Journal of Clinical Oncology, Vol. 22, No. 11, 2004, pp. 2084-2091. doi:10.1200/JCO.2004.11.069
[39]	J. Cassidy, S. Clarke, E. Diaz-Rubio, W. Scheithauer, A. Figer, R. Wong, S. Koski, M. Lichinitser, T. S. Yang, F. Rivera, F. Couture, F. Sirzen and L. Saltz, “Randomized Phase III Study of Capecitabine plus Oxaliplatin Compared with Fluorouracil/Folinic Acid Plus Oxaliplatin as First-Line Therapy for Metastatic Colorectal Cancer,” Journal of Clinical Oncology, Vol. 26, No. 12, 2008, pp. 2006-2012. doi:10.1200/JCO.2007.14.9898
[40]	M. A. Choti, J. V. Sitzmann, M. F. Tiburi, W. Sumetchotimetha, R. Rangsin, R. D. Schulick, K. D. Lillemoe, C. J. Yeo and J. L. Cameron, “Trends in Long-Term Survival following Liver Resection for Hepatic Colorectal Metastases,” Annals of Surgery, Vol. 235, No. 6, 2002, pp. 759-766. doi:10.1097/00000658-200206000-00002
[41]	G. Chong and D. Cunningham, “Improving Long-Term Outcomes for Patients with Liver Metastases from Colorectal Cancer,” Journal of Clinical Oncology, Vol. 23, No. 36, 2005, pp. 9063-9066. doi:10.1200/JCO.2005.04.4669
[42]	V. Cappelletti, P. Miodini, G. Di Fronzo and M. G. Daidone, “Modulation of Estrogen Receptor-Beta Isoforms by Phytoestrogens in Breast Cancer Cells,” International Journal of Oncology, Vol. 28, No. 5, 2006, pp. 1185-1191.
[43]	M. J. Weyant, A. M. Carothers, N. N. Mahmoud, H. L. Bradlow, H. Remotti, R. T. Bilinski and M. M. Bertagnolli, “Reciprocal Expression of ERalpha and ERbeta Is Associated with Estrogen-Mediated Modulation of Intestinal Tumorigenesis,” Cancer Research, Vol. 61, No. 6, 2001, pp. 2547-2551.
[44]	F. Caiazza, P. Galluzzo, S. Lorenzetti and M. Marino, “17Beta-Estradiol Induces ERbeta Up-Regulation via p38/MAPK Activation in Colon Cancer Cells,” Biochemical and Biophysical Research Communications, Vol. 359, No. 1, 2007, pp. 102-107. doi:10.1016/j.bbrc.2007.05.059