Histopathology 2014, 64, 787–790. DOI: 10.1111/his.12340
Oestrogen receptor-beta as a potential target for treatment in advanced colorectal cancer: a pilot study Henk van Halteren, Dries Mulder1 & Emiel Ruijter1 Department of Internal Medicine, Admiraal de Ruijter Hospital, Goes, the Netherlands, and 1Department of Pathology, Rijnstate Hospital, Arnhem, the Netherlands Date of submission 18 September 2013 Accepted for publication 30 November 2013 Published online Article Accepted 3 December 2013
van Halteren H K, Mulder D & Ruijter E (2014) Histopathology 64, 787–790
Oestrogen receptor-beta as a potential target for treatment in advanced colorectal cancer: a pilot study Aims: Oestrogen receptor-beta (ER-b) is expressed in colorectal cancer. Theoretically, ER-b stimulation could slow down tumour proliferation, and this is supported by preclinical research data. While preparing a Phase II trial for advanced colorectal cancer patients we performed a pilot study with three questions: (i) in what percentage of patients do metastases display strong ER-b1 expression; (ii) is there any concordance in expression between primary tumours and metastases; and (iii) is the immunohistochemical (IHC) scoring procedure reproducible? Methods and results: Thirty patients were selected, 15 with locoregional lymph node metastases and 15 with either synchronous or metachronous hepatic
metastases. All primary tumours and metastases were analysed for immunohistochemical ER-b1 expression according to a predefined scoring system. The scoring was performed independently by two pathologists in order to calculate the weighted kappa value. Strong ER-b1 expression was found in four of 15 hepatic metastases and four of 15 lymph node metastases. In 15 of 30 patients, the level of ER-b1 expression in the metastasis was concordant with that observed in the primary tumour. Weighted kappa values of IHC ER-b1 expression were satisfactory. Conclusions: In twenty-five per cent of patients there was strong ER-b1 expression in metastases, biopsy of which will be considered mandatory for trial inclusion.
Keywords: colorectal cancer, metastasis, oestrogen receptor-beta, targeted therapy
Introduction The incidence of colorectal cancer is known to be lower in women compared to men.1–3 Lifetime colorectal cancer risk has also been shown to be lower in women with inherited microsatellite instability (30% in women compared to 74% in men).4 The fact that colorectal cancer risk decreases by at least 30% with oestrogen supplementation has led to the hypothesis that colorectal carcinogenesis can be influenced by sex hormones.5 In the past 15 years oestrogenAddress for correspondence: H van Halteren, Department of Internal Medicine, Admiraal de Ruijter Hospital, ’s Gravenpolderseweg 114, 4460BB Goes, the Netherlands. e-mail: [email protected] © 2013 John Wiley & Sons Ltd.
receptor-beta (ER-b) has been shown to play an active role in the colorectal epithelium. The encoding gene (cloned for the first time in 1996) is located on chromosome 14, whereas the encoding gene for ER-a is located on chromosome 6. Oestrogens and selective oestrogen response modifiers (SERMS), such as tamoxifen and raloxifene, can bind to ER-a and ER-b, which results in up- or down-regulation of oestrogenresponsive genes. Whereas SERMS have an antagonistic effect on ER-a, they display agonistic activity towards ER-b. Oestrogens display an agonistic effect while binding to both ER-a and ER-b. ER-a is expressed in the urogenital tract, the breast, the central nervous system, the liver and bone. ER-b is expressed in the urogenital tract, the breast, blood vessels, the central nervous system, the gastrointestinal tract and bone.
788
H van Halteren et al.
Basic research suggests that ER-b plays a major role in the preservation of organ function.6 In the face of experimental tissue ischaemia, ER-b expression in smooth muscle and endothelium increases, whereas ER-a expression remains unchanged, an interesting phenomenon with regard to the relation between menopausal status and cardiovascular risk.7 ER-b appears to have a protective role against colorectal cancer development. A decrease in ER-b messenger RNA has been related to colon carcinogenesis in women.8 In the transitional phase from normal epithelium through adenoma towards cancer ER-b expression has been shown to decrease. Despite this, up to 80% of colorectal adenocarcinomas show ER-b expression.9 There are five isoforms of ER-b (ER-b1–5). ER-b1 is considered as the key receptor, and simultaneous activation of the other isoforms can augment ER-b1 signal transduction through dimerization or heteromization.10 In colon cancer, high ER-b expression is associated with lower tumour stage, increased tumour cell apoptosis and significantly better prognosis (5 years survival rate 84.3% versus 63.9%, P < 0.05).9,11–15 Theoretically, targeted therapy with ER-b agonists could be beneficial for patients with (advanced) colorectal cancer, and preclinical research suggests that this might indeed be the case. Incubation of the DLD1 adenocarcinoma cell line with phyto-oestrogens has been shown to slow down tumour cell proliferation.16 In ovariectomized mice, 17b-oestradiol down-regulated ER-a and up-regulated ER-b in colonic epithelium.17 Incubation with either SERMS or oestradiol leads to significant ER-b-mediated growth inhibition in several tumour cell lines.18–21 Based on these findings, we developed a Phase II study protocol which aims to estimate the effect of treatment with raloxifene in patients with advanced ER-b-positive colorectal cancer. However, we could not find publications regarding ER-b expression in colorectal cancer metastases. Furthermore, we did not find any reports on ER-b-targeted therapy in the literature. In preparation for a future Phase II trial, we conducted a pilot study to estimate the prevalence and intensity of ER-b1 expression in primary colorectal cancer. Furthermore, the concordance in ER-b1 expression between primary tumours and hepatic/ lymphatic metastases was analysed.
Patients and methods Fifteen patients with lymph node-positive colorectal cancer and 15 patients who had undergone resection
of isolated hepatic metastases were selected from the pathology database of our hospital. IMMUNOHISTOCHEMISTRY AND QUANTIFICATION
Representative paraffin-embedded tissues (containing vital tumour) from the primary tumour (n = 30) and the metastasis (lymph node n = 15, liver metastasis n = 15) were selected; 4-lm sections were stained immunohistochemically for ER-b1 using an immunostainer (BondMax; Leica Biosystems Ltd, Newcastle upon Tyne, UK). After deparaffinization the slides were incubated with the human anti-ERb1 clone (PPG 5/10; DakoCytomation, Glostrup, Denmark) diluted 1:20. This procedure was followed by washing, polymer detection (DAB) and haematoxylin counterstaining. Adjacent normal tissue was stained for control purposes. A tumour cell was considered ER-b1-positive if it showed nuclear staining. The product of the percentage positively staining cells (0–100) and the staining intensity (on a 0–3 scale) was calculated. The final staining score was defined as follows: poor staining = score 0–100; intermediate staining = score 101–200, strong staining = score 201–300. The scores were repeated independently by a second pathologist in order to calculate the weighted kappa value.
Results Sections from the thirty primary tumour samples, 15 lymph node metastases and 15 hepatic metastases were examined independently by two pathologists. Weighted kappa values for ER-b expression analysis were 0.704, 0.769 and 0.759, respectively. Figure 1 shows two primary tumour specimens displaying poor and strong ER-b1 expression, respectively. Of the 15 lymph node metastases, seven displayed poor ER-b1 expression, four intermediate expression, and four strong expression (Table 1). In eight of 15 cases (including two patients with strong ER-b1 expression), the staining intensity of the primary tumour and lymph node metastasis was comparable, but for the remaining seven cases the staining scores for primary tumour and metastasis differed considerably; in four patients an intensity decrease from primary tumour towards metastasis was seen, and in three patients an intensity increase was seen. Four of the 15 hepatic metastases displayed strong ER-b1 expression (Table 2). In seven of 15 cases (including three patients with strong ER-b1 expression), the staining intensity of the primary tumour © 2013 John Wiley & Sons Ltd, Histopathology, 64, 787–790.
Oestrogen receptor-beta and colorectal cancer
789
Table 1. Nuclear ER-b1 staining intensity for 15 patients with node-positive colorectal cancer: primary tumour versus lymph node metastasis Patient number
Figure 1. Immunohistochemical ER-b expression in (upper) poorly and (lower) strongly staining primary colorectal adenocarcinomas.
and hepatic metastasis was comparable, but for the remaining eight cases the staining scores for primary tumour and liver metastasis differed considerably; the majority (n = 6) displayed an intensity decrease from primary tumour towards metastasis.
Discussion The results of preclinical research suggest that ER-b-directed therapy could slow tumour growth in colorectal cancer. We are planning an ER-b-targeting Phase II trial with raloxifene for patients with chemorefractory advanced colorectal cancer or a contraindication for chemotherapy. Trial inclusion and outcome would benefit greatly from a practical and reproducible procedure to estimate the degree of ER-b expression. A biopsy of the metastasis would be the most suitable material for analysis. Phenotypical assessment is feasible, but could be complicated © 2013 John Wiley & Sons Ltd, Histopathology, 64, 787–790.
Primary tumour
Lymph node metastasis
1
Poor
Poor
2
Intermediate
Intermediate
3
Poor
Poor
4
Strong
Strong
5
Strong
Intermediate
6
Poor
Poor
7
Poor
Intermediate
8
Intermediate
Intermediate
9
Intermediate
Poor
10
Poor
Poor
11
Intermediate
Poor
12
Intermediate
Strong
13
Strong
Strong
14
Strong
Poor
15
Poor
Strong
by poor reproducibility. Molecular assessment is reproducible, but would require more laborious biopsy handling and a more costly testing procedure. In the present study we estimated ER-b1 expression intensity in primary tumours, lymph node metastases and hepatic metastases. The reproducibility of immunohistochemical ER-b1 expression intensity measurement appeared satisfactory. The majority of lymph node and hepatic metastases displayed ER-b1, and there was no clear trend towards decreased expression when primary tumour and metastasis were compared. With regard to a future ER-b-targeted Phase II trial we made the basic assumption that, initially, only patients with metastases displaying strong ER-b1 expression would be included. Based on our findings, approximately 25% of patients with advanced colorectal cancer could be eligible. For trial inclusion, biopsy from a metastatic site will be considered mandatory, as there was limited (15 of 30 patients) concordance between ER-b1 expression intensity in primary tumour and metastasis.
790
H van Halteren et al.
Table 2. Nuclear ER-b1 staining intensity for 15 patients with colorectal cancer and liver metastases: primary tumour versus hepatic metastasis Patient number
Primary tumour
Hepatic metastasis
1
Poor
Strong
2
Strong
Poor
3
Poor
Poor
4
Intermediate
Intermediate
5
Strong
Poor
6
Poor
Poor
7
Poor
Poor
8
Strong
Strong
9
Strong
Poor
10
Strong
Strong
11
Intermediate
Poor
12
Strong
Strong
13
Poor
Intermediate
14
Intermediate
Poor
15
Intermediate
Poor
Conflict of interest None to declare.
References 1. DeCosse JJ, Ngoi SS, Jacobson J, Cennerazzo WJ. Gender and colorectal cancer. Eur. J. Cancer Prev. 1993; 2; 105–115. 2. Ries LA, Wingo P, Miller DS et al. The annual report to the nation on the status of cancer, 1973–1997. Cancer 2000; 88; 2398–2424. 3. Barone M, Tanzi S, Lofano K et al. Estrogens, phytoestrogens and colorectal neoproliferative lesions. Genes Nutr. 2008; 3; 7– 13. 4. Froggatt NJ, Green J, Brassett C et al. A common MSH2 mutation in English and North American HNPCC families: origin, phenotypic expression and sex-specific differences in colorectal cancer. J. Med. Genet. 1999; 36; 97–102. 5. Crandall C. Estrogen replacement therapy and colon cancer: a clinical review. J. Womens Health Gend. Based Med. 1999; 8; 1155–1166.
6. Heldring A, Pike A, Andersson S et al. Estrogen receptors: how do they signal and what are their targets. Physiol. Rev. 2007; 87; 905–931. 7. Iafrati MD, Karas RH, Aronvitz M et al. Estrogen inhibits the vascular injury response in estrogen receptora-deficient mice. Nat. Med. 2009; 3; 545–548. 8. Campbell-Thompson M, Lynch J, Bhardwaj B. Expression of estrogen receptor subtypes and ERb isoforms in colon cancer. Cancer Res. 2001; 61; 632–640. 9. Jassam N, Bell SM, Speirs V, Quirke P. Loss of expression of oestrogen receptor beta in colon cancer cells and its association with Dukes’ staging. Oncol. Rep. 2005; 14; 17–21. 10. Leung Y, Mak P, Hassan S, Ho S. Estrogen receptor (ER)-b isoforms: a key to understanding ER-b signaling. Proc. Natl Acad. Sci. USA 2006; 103; 13162–13167. 11. Fang YJ, Lu ZH, Wang F et al. Prognostic impact of ERb and MMP7 expression on overall survival in colon cancer. Tumour Biol. 2010; 31; 651–658. 12. Fang YJ, Zhang L, Wu XJ et al. Impact of ERb and CD44 expression on the prognosis of patients with stage II colon cancer. Tumour Biol. 2012; 33; 1907–1914. 13. Taggarshe D, Lobocki C, Silberberg B, McKendrick A, Mittal VK. Clinicopathological significance of the expression of estrogen receptor beta and vascular endothelial growth factor-A in colorectal cancer. Am. Surg. 2012; 78; 1376–1382. 14. Elbanna HG, Ebrahim MA, Abbas AM, Zalata K, Hashim MA. Potential value of estrogen receptor beta expression in colorectal carcinoma: interaction with apoptotic index. J. Gastrointest. Cancer 2012; 43; 56–62. 15. Rudolph A, Toth C, Hoffmeister M et al. Expression of oestrogen receptor b and prognosis of colorectal cancer. Br. J. Cancer 2012; 107; 831–839. 16. Bielecki A, Roberts J, Mehta R, Raju J. Estrogen receptor-b mediates the inhibition of DLD-1 human adenocarcinoma cells by soy isoflavones. Nutr. Cancer 2011; 63; 139–150. 17. Weyant MJ, Carothers AM, Mahmoud NN, Bradlow HL, Remotti H, Bilinski RT. Reciprocal expression of ERalpha and ERbeta is associated with estrogen-mediated modulation of intestinal tumorigenesis. Cancer Res. 2001; 61; 2547–2551. 18. Nakayama Y, Sakamoto H, Satoh K, Yamamoto T. Tamoxifen and gonadal steroids inhibit colon cancer growth in association with inhibition of thymidilate synthase, survivin and telomerase expression through estrogen receptor beta mediated system. Cancer Lett. 2000; 161; 63–71. 19. Picariello L, Fiorelli G, Martineti V, Tognarini I, Pampaloni B, Tonelli F. Growth response of colon cancer cell lines to selective estrogen response receptor modulators. Anticancer Res. 2003; 23; 2419–2424. 20. Tu Z, Ma Y, Tian J et al. Estrogen receptor b potentiates the antiproliferative effect of raloxifene or tamoxifen and affects the cell migration and invasion in HCT-116 coloncarcer cells. J. Cancer Res. Clin. Oncol. 2012; 138; 1091–1103. 21. Yu-Xi H, Jian-Qiu S, Xian-Long L et al. Estradiol regulates miR135b and mismatch repair expressions via estrogen receptor b in colorectal cells. Exp. Mol. Med. 2012; 4; 723–732.
© 2013 John Wiley & Sons Ltd, Histopathology, 64, 787–790.
Oestrogen receptor-beta as a potential target for treatment in advanced colorectal cancer: a pilot study Henk van Halteren, Dries Mulder1 & Emiel Ruijter1 Department of Internal Medicine, Admiraal de Ruijter Hospital, Goes, the Netherlands, and 1Department of Pathology, Rijnstate Hospital, Arnhem, the Netherlands Date of submission 18 September 2013 Accepted for publication 30 November 2013 Published online Article Accepted 3 December 2013
van Halteren H K, Mulder D & Ruijter E (2014) Histopathology 64, 787–790
Oestrogen receptor-beta as a potential target for treatment in advanced colorectal cancer: a pilot study Aims: Oestrogen receptor-beta (ER-b) is expressed in colorectal cancer. Theoretically, ER-b stimulation could slow down tumour proliferation, and this is supported by preclinical research data. While preparing a Phase II trial for advanced colorectal cancer patients we performed a pilot study with three questions: (i) in what percentage of patients do metastases display strong ER-b1 expression; (ii) is there any concordance in expression between primary tumours and metastases; and (iii) is the immunohistochemical (IHC) scoring procedure reproducible? Methods and results: Thirty patients were selected, 15 with locoregional lymph node metastases and 15 with either synchronous or metachronous hepatic
metastases. All primary tumours and metastases were analysed for immunohistochemical ER-b1 expression according to a predefined scoring system. The scoring was performed independently by two pathologists in order to calculate the weighted kappa value. Strong ER-b1 expression was found in four of 15 hepatic metastases and four of 15 lymph node metastases. In 15 of 30 patients, the level of ER-b1 expression in the metastasis was concordant with that observed in the primary tumour. Weighted kappa values of IHC ER-b1 expression were satisfactory. Conclusions: In twenty-five per cent of patients there was strong ER-b1 expression in metastases, biopsy of which will be considered mandatory for trial inclusion.
Keywords: colorectal cancer, metastasis, oestrogen receptor-beta, targeted therapy
Introduction The incidence of colorectal cancer is known to be lower in women compared to men.1–3 Lifetime colorectal cancer risk has also been shown to be lower in women with inherited microsatellite instability (30% in women compared to 74% in men).4 The fact that colorectal cancer risk decreases by at least 30% with oestrogen supplementation has led to the hypothesis that colorectal carcinogenesis can be influenced by sex hormones.5 In the past 15 years oestrogenAddress for correspondence: H van Halteren, Department of Internal Medicine, Admiraal de Ruijter Hospital, ’s Gravenpolderseweg 114, 4460BB Goes, the Netherlands. e-mail: [email protected] © 2013 John Wiley & Sons Ltd.
receptor-beta (ER-b) has been shown to play an active role in the colorectal epithelium. The encoding gene (cloned for the first time in 1996) is located on chromosome 14, whereas the encoding gene for ER-a is located on chromosome 6. Oestrogens and selective oestrogen response modifiers (SERMS), such as tamoxifen and raloxifene, can bind to ER-a and ER-b, which results in up- or down-regulation of oestrogenresponsive genes. Whereas SERMS have an antagonistic effect on ER-a, they display agonistic activity towards ER-b. Oestrogens display an agonistic effect while binding to both ER-a and ER-b. ER-a is expressed in the urogenital tract, the breast, the central nervous system, the liver and bone. ER-b is expressed in the urogenital tract, the breast, blood vessels, the central nervous system, the gastrointestinal tract and bone.
788
H van Halteren et al.
Basic research suggests that ER-b plays a major role in the preservation of organ function.6 In the face of experimental tissue ischaemia, ER-b expression in smooth muscle and endothelium increases, whereas ER-a expression remains unchanged, an interesting phenomenon with regard to the relation between menopausal status and cardiovascular risk.7 ER-b appears to have a protective role against colorectal cancer development. A decrease in ER-b messenger RNA has been related to colon carcinogenesis in women.8 In the transitional phase from normal epithelium through adenoma towards cancer ER-b expression has been shown to decrease. Despite this, up to 80% of colorectal adenocarcinomas show ER-b expression.9 There are five isoforms of ER-b (ER-b1–5). ER-b1 is considered as the key receptor, and simultaneous activation of the other isoforms can augment ER-b1 signal transduction through dimerization or heteromization.10 In colon cancer, high ER-b expression is associated with lower tumour stage, increased tumour cell apoptosis and significantly better prognosis (5 years survival rate 84.3% versus 63.9%, P < 0.05).9,11–15 Theoretically, targeted therapy with ER-b agonists could be beneficial for patients with (advanced) colorectal cancer, and preclinical research suggests that this might indeed be the case. Incubation of the DLD1 adenocarcinoma cell line with phyto-oestrogens has been shown to slow down tumour cell proliferation.16 In ovariectomized mice, 17b-oestradiol down-regulated ER-a and up-regulated ER-b in colonic epithelium.17 Incubation with either SERMS or oestradiol leads to significant ER-b-mediated growth inhibition in several tumour cell lines.18–21 Based on these findings, we developed a Phase II study protocol which aims to estimate the effect of treatment with raloxifene in patients with advanced ER-b-positive colorectal cancer. However, we could not find publications regarding ER-b expression in colorectal cancer metastases. Furthermore, we did not find any reports on ER-b-targeted therapy in the literature. In preparation for a future Phase II trial, we conducted a pilot study to estimate the prevalence and intensity of ER-b1 expression in primary colorectal cancer. Furthermore, the concordance in ER-b1 expression between primary tumours and hepatic/ lymphatic metastases was analysed.
Patients and methods Fifteen patients with lymph node-positive colorectal cancer and 15 patients who had undergone resection
of isolated hepatic metastases were selected from the pathology database of our hospital. IMMUNOHISTOCHEMISTRY AND QUANTIFICATION
Representative paraffin-embedded tissues (containing vital tumour) from the primary tumour (n = 30) and the metastasis (lymph node n = 15, liver metastasis n = 15) were selected; 4-lm sections were stained immunohistochemically for ER-b1 using an immunostainer (BondMax; Leica Biosystems Ltd, Newcastle upon Tyne, UK). After deparaffinization the slides were incubated with the human anti-ERb1 clone (PPG 5/10; DakoCytomation, Glostrup, Denmark) diluted 1:20. This procedure was followed by washing, polymer detection (DAB) and haematoxylin counterstaining. Adjacent normal tissue was stained for control purposes. A tumour cell was considered ER-b1-positive if it showed nuclear staining. The product of the percentage positively staining cells (0–100) and the staining intensity (on a 0–3 scale) was calculated. The final staining score was defined as follows: poor staining = score 0–100; intermediate staining = score 101–200, strong staining = score 201–300. The scores were repeated independently by a second pathologist in order to calculate the weighted kappa value.
Results Sections from the thirty primary tumour samples, 15 lymph node metastases and 15 hepatic metastases were examined independently by two pathologists. Weighted kappa values for ER-b expression analysis were 0.704, 0.769 and 0.759, respectively. Figure 1 shows two primary tumour specimens displaying poor and strong ER-b1 expression, respectively. Of the 15 lymph node metastases, seven displayed poor ER-b1 expression, four intermediate expression, and four strong expression (Table 1). In eight of 15 cases (including two patients with strong ER-b1 expression), the staining intensity of the primary tumour and lymph node metastasis was comparable, but for the remaining seven cases the staining scores for primary tumour and metastasis differed considerably; in four patients an intensity decrease from primary tumour towards metastasis was seen, and in three patients an intensity increase was seen. Four of the 15 hepatic metastases displayed strong ER-b1 expression (Table 2). In seven of 15 cases (including three patients with strong ER-b1 expression), the staining intensity of the primary tumour © 2013 John Wiley & Sons Ltd, Histopathology, 64, 787–790.
Oestrogen receptor-beta and colorectal cancer
789
Table 1. Nuclear ER-b1 staining intensity for 15 patients with node-positive colorectal cancer: primary tumour versus lymph node metastasis Patient number
Figure 1. Immunohistochemical ER-b expression in (upper) poorly and (lower) strongly staining primary colorectal adenocarcinomas.
and hepatic metastasis was comparable, but for the remaining eight cases the staining scores for primary tumour and liver metastasis differed considerably; the majority (n = 6) displayed an intensity decrease from primary tumour towards metastasis.
Discussion The results of preclinical research suggest that ER-b-directed therapy could slow tumour growth in colorectal cancer. We are planning an ER-b-targeting Phase II trial with raloxifene for patients with chemorefractory advanced colorectal cancer or a contraindication for chemotherapy. Trial inclusion and outcome would benefit greatly from a practical and reproducible procedure to estimate the degree of ER-b expression. A biopsy of the metastasis would be the most suitable material for analysis. Phenotypical assessment is feasible, but could be complicated © 2013 John Wiley & Sons Ltd, Histopathology, 64, 787–790.
Primary tumour
Lymph node metastasis
1
Poor
Poor
2
Intermediate
Intermediate
3
Poor
Poor
4
Strong
Strong
5
Strong
Intermediate
6
Poor
Poor
7
Poor
Intermediate
8
Intermediate
Intermediate
9
Intermediate
Poor
10
Poor
Poor
11
Intermediate
Poor
12
Intermediate
Strong
13
Strong
Strong
14
Strong
Poor
15
Poor
Strong
by poor reproducibility. Molecular assessment is reproducible, but would require more laborious biopsy handling and a more costly testing procedure. In the present study we estimated ER-b1 expression intensity in primary tumours, lymph node metastases and hepatic metastases. The reproducibility of immunohistochemical ER-b1 expression intensity measurement appeared satisfactory. The majority of lymph node and hepatic metastases displayed ER-b1, and there was no clear trend towards decreased expression when primary tumour and metastasis were compared. With regard to a future ER-b-targeted Phase II trial we made the basic assumption that, initially, only patients with metastases displaying strong ER-b1 expression would be included. Based on our findings, approximately 25% of patients with advanced colorectal cancer could be eligible. For trial inclusion, biopsy from a metastatic site will be considered mandatory, as there was limited (15 of 30 patients) concordance between ER-b1 expression intensity in primary tumour and metastasis.
790
H van Halteren et al.
Table 2. Nuclear ER-b1 staining intensity for 15 patients with colorectal cancer and liver metastases: primary tumour versus hepatic metastasis Patient number
Primary tumour
Hepatic metastasis
1
Poor
Strong
2
Strong
Poor
3
Poor
Poor
4
Intermediate
Intermediate
5
Strong
Poor
6
Poor
Poor
7
Poor
Poor
8
Strong
Strong
9
Strong
Poor
10
Strong
Strong
11
Intermediate
Poor
12
Strong
Strong
13
Poor
Intermediate
14
Intermediate
Poor
15
Intermediate
Poor
Conflict of interest None to declare.
References 1. DeCosse JJ, Ngoi SS, Jacobson J, Cennerazzo WJ. Gender and colorectal cancer. Eur. J. Cancer Prev. 1993; 2; 105–115. 2. Ries LA, Wingo P, Miller DS et al. The annual report to the nation on the status of cancer, 1973–1997. Cancer 2000; 88; 2398–2424. 3. Barone M, Tanzi S, Lofano K et al. Estrogens, phytoestrogens and colorectal neoproliferative lesions. Genes Nutr. 2008; 3; 7– 13. 4. Froggatt NJ, Green J, Brassett C et al. A common MSH2 mutation in English and North American HNPCC families: origin, phenotypic expression and sex-specific differences in colorectal cancer. J. Med. Genet. 1999; 36; 97–102. 5. Crandall C. Estrogen replacement therapy and colon cancer: a clinical review. J. Womens Health Gend. Based Med. 1999; 8; 1155–1166.
6. Heldring A, Pike A, Andersson S et al. Estrogen receptors: how do they signal and what are their targets. Physiol. Rev. 2007; 87; 905–931. 7. Iafrati MD, Karas RH, Aronvitz M et al. Estrogen inhibits the vascular injury response in estrogen receptora-deficient mice. Nat. Med. 2009; 3; 545–548. 8. Campbell-Thompson M, Lynch J, Bhardwaj B. Expression of estrogen receptor subtypes and ERb isoforms in colon cancer. Cancer Res. 2001; 61; 632–640. 9. Jassam N, Bell SM, Speirs V, Quirke P. Loss of expression of oestrogen receptor beta in colon cancer cells and its association with Dukes’ staging. Oncol. Rep. 2005; 14; 17–21. 10. Leung Y, Mak P, Hassan S, Ho S. Estrogen receptor (ER)-b isoforms: a key to understanding ER-b signaling. Proc. Natl Acad. Sci. USA 2006; 103; 13162–13167. 11. Fang YJ, Lu ZH, Wang F et al. Prognostic impact of ERb and MMP7 expression on overall survival in colon cancer. Tumour Biol. 2010; 31; 651–658. 12. Fang YJ, Zhang L, Wu XJ et al. Impact of ERb and CD44 expression on the prognosis of patients with stage II colon cancer. Tumour Biol. 2012; 33; 1907–1914. 13. Taggarshe D, Lobocki C, Silberberg B, McKendrick A, Mittal VK. Clinicopathological significance of the expression of estrogen receptor beta and vascular endothelial growth factor-A in colorectal cancer. Am. Surg. 2012; 78; 1376–1382. 14. Elbanna HG, Ebrahim MA, Abbas AM, Zalata K, Hashim MA. Potential value of estrogen receptor beta expression in colorectal carcinoma: interaction with apoptotic index. J. Gastrointest. Cancer 2012; 43; 56–62. 15. Rudolph A, Toth C, Hoffmeister M et al. Expression of oestrogen receptor b and prognosis of colorectal cancer. Br. J. Cancer 2012; 107; 831–839. 16. Bielecki A, Roberts J, Mehta R, Raju J. Estrogen receptor-b mediates the inhibition of DLD-1 human adenocarcinoma cells by soy isoflavones. Nutr. Cancer 2011; 63; 139–150. 17. Weyant MJ, Carothers AM, Mahmoud NN, Bradlow HL, Remotti H, Bilinski RT. Reciprocal expression of ERalpha and ERbeta is associated with estrogen-mediated modulation of intestinal tumorigenesis. Cancer Res. 2001; 61; 2547–2551. 18. Nakayama Y, Sakamoto H, Satoh K, Yamamoto T. Tamoxifen and gonadal steroids inhibit colon cancer growth in association with inhibition of thymidilate synthase, survivin and telomerase expression through estrogen receptor beta mediated system. Cancer Lett. 2000; 161; 63–71. 19. Picariello L, Fiorelli G, Martineti V, Tognarini I, Pampaloni B, Tonelli F. Growth response of colon cancer cell lines to selective estrogen response receptor modulators. Anticancer Res. 2003; 23; 2419–2424. 20. Tu Z, Ma Y, Tian J et al. Estrogen receptor b potentiates the antiproliferative effect of raloxifene or tamoxifen and affects the cell migration and invasion in HCT-116 coloncarcer cells. J. Cancer Res. Clin. Oncol. 2012; 138; 1091–1103. 21. Yu-Xi H, Jian-Qiu S, Xian-Long L et al. Estradiol regulates miR135b and mismatch repair expressions via estrogen receptor b in colorectal cells. Exp. Mol. Med. 2012; 4; 723–732.
© 2013 John Wiley & Sons Ltd, Histopathology, 64, 787–790.
