604
Geng Bian and Wen-Ying Zhao
DOI: 10.1002/eji.201343875
Eur. J. Immunol. 2014. 44: 604–605
Letter to the Editor [DOI: 10.1002/eji.201343875]
To the Editor IL-17, an important prognostic factor and potential therapeutic target for breast cancer? We read with great interest an article published in the European Journal of Immunology [1], showing that the Th17-related molecules IL-17 and Retinoid-related orphan receptor (ROR) C were elevated in tumor-infiltrating CD4+ and CD8+ T lymphocytes in breast cancer patients. The authors went on to show that angiogenic factors CXCL8, MMP-2, MMP-9, and vascular endothelial growth factor detected within the tumor were possibly induced by IL-17 and indicative of poor disease prognosis [1]. Finally, Th17 cells were also shown to be simultaneously upregulated in breast cancer patients, positively correlated with IL-17, and associated with tumor aggressiveness [1]. These findings suggest that a high level of IL-17 in breast cancer is a poor prognostic factor, and IL-17 may be a potential therapeutic target for breast cancer. Breast cancer occurs in approximately 99.4 of every 100 000 women in North America and is the most frequent malignancy in women. The disease is the second
leading cause of mortality due to cancer among women [2]. Despite the large amount of effort that has been devoted to understanding the etiology of breast cancer, the molecular pathogenesis of breast cancer remains poorly understood. Recently, IL-17 mRNA expression was found to be higher in human breast cancer samples compared with healthy breast tissue [3]. Increased numbers of IL-17-producing cells within tissues were related to high histological grade (odds ratio: 4.27, 95% confidence interval: 1.44–12.65, p < 0.01), estrogen receptor/progesterone receptor (PR) negative
status (odds ratio: 3.18, 95% confidence interval: 1.48–6.84, p < 0.01) in breast cancer [4]. Patients with tumors with high numbers of IL-17-producing cells had shorter disease-free survival times than patients with tumors with low numbers of IL-17-producing cells, and high levels IL-17 are a significant prognostic factor for disease-free survival [4]. In Chinese Han women with breast cancer, polymorphism of the rs2275913 in the Il17 gene indicates a higher frequency of the AA genotype in patients than in healthy controls [5]. Analysis of clinical features demonstrated significant
Figure 1. Possible relationship between IL-17 and breast cancer. IL-17 expression has been shown to be higher in breast cancer patients and a murine model of breast cancer compared with healthy controls, respectively. In breast cancer patients, high IL-17 expression can induce the expression of CXCL8, MMP-2, MMP-9, and vascular endothelial growth factor, while in a murine model of breast cancer, recombinant IL-17 injection can increase tumor volume and microvascular density. On the contrary, antagonists such as endothelin-1 receptor dual antagonist and anti-TGF-β antibodies can reduce the levels of TNF-α, IL-17 and thus tumor growth. Furthermore, three single-nucleotide polymorphisms related to breast cancer have been identified.
Correspondence: Dr. Wen-Ying Zhao e-mail: [email protected] C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eji-journal.eu
Eur. J. Immunol. 2014. 44: 604–605
associations between IL-17 singlenucleotide polymorphisms (SNPs) in IL-17 (rs2275913, rs3819025, and rs3748067) and tumor protein 53 (P53), PR, human epidermal growth factor receptor 2, and triple-negative (estrogen receptor/PR/human epidermal growth factor receptor 2) status [5]. In addition, haplotype analysis showed that the frequency of the haplotype Ars2275913 Grs3819025 Grs3748067 , located in the IL-17 linkage disequilibrium block, was higher in breast tumor patients than in healthy controls, suggesting that single-nucleotide polymorphisms in IL-17 are related to the risk of breast cancer. Moreover, it has been shown in murine models of breast cancer that CD8+ splenocytes from tumor-bearing mice express higher levels of IL-17 compared with those from naive mice, and that CD8+ T cells can be induced to make IL-17 on addition of TGF-β and IL-6 [2, 3]. These data suggest that IL-17 is aberrant in both human breast cancer patients and murine models of breast cancer. The injection of 4T1 tumor-bearing mice with recombinant IL-17 resulted in increased tumor volume and microvascular density, as measured by the immunohistochemical detection of CD34 expression in microvessels [2]. Furthermore, IL-17 suppressed apoptosis of several human breast carcinoma cell lines,
Letter to the Editor
such as 4T1, MDA MB231 cells [3]. On the contrary, mice implanted with the carcinoma 4T1 cells and then treated with the endothelin-1 receptor dual antagonist showed decreased levels of TNF-α and IL-17 and reduced tumor growth [6]. Similarly, treatment of mice with anti-TGF-β antibodies reduced IL-17 expression both in the tumor and the locoregional lymph nodes [3]. Consistently, knockdown of the IL-17 receptor in 4T1 mouse mammary cancer cells enhanced apoptosis and decreased tumor growth [3]. Collectively, the available evidence suggests a potential role for IL-17 in breast cancer, and that IL-17 expression may be a poor prognostic factor for breast cancer (Fig. 1). However, further studies are needed to comprehensively explore the role of IL-17 in breast cancer, and the development of therapeutic agents targeting IL-17 [7] may lead to important new, innovative therapies for breast cancer. Geng Bian and Wen-Ying Zhao Department of Medical Oncology, Yijishan Hospital, Wannan Medical College, Wuhu, P.R. China
Conflict of interest: The authors declare no financial or commercial conflict of interest.
C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
References 1 Benevides, L., et al., Eur. J. Immunol. 2013. 43: 1518–1528. 2 Du, J. W., Xu, K. Y., Fang, L. Y. and Qi, X. L., Mol. Med. Rep. 2012. 6: 1099–1102. 3 Nam, J. S., Terabe, M., Kang, M. J., Chae, H., Voong, N., Yang, Y. A., Laurence, A. et al., Cancer Res. 2008. 68: 3915–3923. 4 Chen, W. C., Lai, Y. H., Chen, H. Y., Guo, H. R., Su, I. J. and Chen, H. H., Histopathology. 2013. 63: 225–233. 5 Wang, L., Jiang, Y., Zhang, Y., Wang, Y., Huang, S., Wang, Z., Tian, B. et al., PLoS One 2012. 7: e34400. 6 Jewell, A. N., Swamydas, M., Castillo, C. I., Wyan, H., Allen, L. D., McDermott, K. A., Eddy, J. M. et al., Cancer Invest. 2010. 28: 932– 943. 7 Huh, J. R. and Littman, D. R., Eur. J. Immunol. 2012. 42: 2232–2237.
Full correspondence: Dr. Wen-Ying Zhao, Department of Medical Oncology, Yijishan Hospital, Wannan Medical College, Wuhu, Anhui, 241000, P.R. China Fax: +86-553-3932539 e-mail: [email protected] Received: 4/7/2013 Revised: 10/9/2013 Accepted: 18/9/2013 Accepted article online: 23/10/2013
www.eji-journal.eu
605
Geng Bian and Wen-Ying Zhao
DOI: 10.1002/eji.201343875
Eur. J. Immunol. 2014. 44: 604–605
Letter to the Editor [DOI: 10.1002/eji.201343875]
To the Editor IL-17, an important prognostic factor and potential therapeutic target for breast cancer? We read with great interest an article published in the European Journal of Immunology [1], showing that the Th17-related molecules IL-17 and Retinoid-related orphan receptor (ROR) C were elevated in tumor-infiltrating CD4+ and CD8+ T lymphocytes in breast cancer patients. The authors went on to show that angiogenic factors CXCL8, MMP-2, MMP-9, and vascular endothelial growth factor detected within the tumor were possibly induced by IL-17 and indicative of poor disease prognosis [1]. Finally, Th17 cells were also shown to be simultaneously upregulated in breast cancer patients, positively correlated with IL-17, and associated with tumor aggressiveness [1]. These findings suggest that a high level of IL-17 in breast cancer is a poor prognostic factor, and IL-17 may be a potential therapeutic target for breast cancer. Breast cancer occurs in approximately 99.4 of every 100 000 women in North America and is the most frequent malignancy in women. The disease is the second
leading cause of mortality due to cancer among women [2]. Despite the large amount of effort that has been devoted to understanding the etiology of breast cancer, the molecular pathogenesis of breast cancer remains poorly understood. Recently, IL-17 mRNA expression was found to be higher in human breast cancer samples compared with healthy breast tissue [3]. Increased numbers of IL-17-producing cells within tissues were related to high histological grade (odds ratio: 4.27, 95% confidence interval: 1.44–12.65, p < 0.01), estrogen receptor/progesterone receptor (PR) negative
status (odds ratio: 3.18, 95% confidence interval: 1.48–6.84, p < 0.01) in breast cancer [4]. Patients with tumors with high numbers of IL-17-producing cells had shorter disease-free survival times than patients with tumors with low numbers of IL-17-producing cells, and high levels IL-17 are a significant prognostic factor for disease-free survival [4]. In Chinese Han women with breast cancer, polymorphism of the rs2275913 in the Il17 gene indicates a higher frequency of the AA genotype in patients than in healthy controls [5]. Analysis of clinical features demonstrated significant
Figure 1. Possible relationship between IL-17 and breast cancer. IL-17 expression has been shown to be higher in breast cancer patients and a murine model of breast cancer compared with healthy controls, respectively. In breast cancer patients, high IL-17 expression can induce the expression of CXCL8, MMP-2, MMP-9, and vascular endothelial growth factor, while in a murine model of breast cancer, recombinant IL-17 injection can increase tumor volume and microvascular density. On the contrary, antagonists such as endothelin-1 receptor dual antagonist and anti-TGF-β antibodies can reduce the levels of TNF-α, IL-17 and thus tumor growth. Furthermore, three single-nucleotide polymorphisms related to breast cancer have been identified.
Correspondence: Dr. Wen-Ying Zhao e-mail: [email protected] C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eji-journal.eu
Eur. J. Immunol. 2014. 44: 604–605
associations between IL-17 singlenucleotide polymorphisms (SNPs) in IL-17 (rs2275913, rs3819025, and rs3748067) and tumor protein 53 (P53), PR, human epidermal growth factor receptor 2, and triple-negative (estrogen receptor/PR/human epidermal growth factor receptor 2) status [5]. In addition, haplotype analysis showed that the frequency of the haplotype Ars2275913 Grs3819025 Grs3748067 , located in the IL-17 linkage disequilibrium block, was higher in breast tumor patients than in healthy controls, suggesting that single-nucleotide polymorphisms in IL-17 are related to the risk of breast cancer. Moreover, it has been shown in murine models of breast cancer that CD8+ splenocytes from tumor-bearing mice express higher levels of IL-17 compared with those from naive mice, and that CD8+ T cells can be induced to make IL-17 on addition of TGF-β and IL-6 [2, 3]. These data suggest that IL-17 is aberrant in both human breast cancer patients and murine models of breast cancer. The injection of 4T1 tumor-bearing mice with recombinant IL-17 resulted in increased tumor volume and microvascular density, as measured by the immunohistochemical detection of CD34 expression in microvessels [2]. Furthermore, IL-17 suppressed apoptosis of several human breast carcinoma cell lines,
Letter to the Editor
such as 4T1, MDA MB231 cells [3]. On the contrary, mice implanted with the carcinoma 4T1 cells and then treated with the endothelin-1 receptor dual antagonist showed decreased levels of TNF-α and IL-17 and reduced tumor growth [6]. Similarly, treatment of mice with anti-TGF-β antibodies reduced IL-17 expression both in the tumor and the locoregional lymph nodes [3]. Consistently, knockdown of the IL-17 receptor in 4T1 mouse mammary cancer cells enhanced apoptosis and decreased tumor growth [3]. Collectively, the available evidence suggests a potential role for IL-17 in breast cancer, and that IL-17 expression may be a poor prognostic factor for breast cancer (Fig. 1). However, further studies are needed to comprehensively explore the role of IL-17 in breast cancer, and the development of therapeutic agents targeting IL-17 [7] may lead to important new, innovative therapies for breast cancer. Geng Bian and Wen-Ying Zhao Department of Medical Oncology, Yijishan Hospital, Wannan Medical College, Wuhu, P.R. China
Conflict of interest: The authors declare no financial or commercial conflict of interest.
C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
References 1 Benevides, L., et al., Eur. J. Immunol. 2013. 43: 1518–1528. 2 Du, J. W., Xu, K. Y., Fang, L. Y. and Qi, X. L., Mol. Med. Rep. 2012. 6: 1099–1102. 3 Nam, J. S., Terabe, M., Kang, M. J., Chae, H., Voong, N., Yang, Y. A., Laurence, A. et al., Cancer Res. 2008. 68: 3915–3923. 4 Chen, W. C., Lai, Y. H., Chen, H. Y., Guo, H. R., Su, I. J. and Chen, H. H., Histopathology. 2013. 63: 225–233. 5 Wang, L., Jiang, Y., Zhang, Y., Wang, Y., Huang, S., Wang, Z., Tian, B. et al., PLoS One 2012. 7: e34400. 6 Jewell, A. N., Swamydas, M., Castillo, C. I., Wyan, H., Allen, L. D., McDermott, K. A., Eddy, J. M. et al., Cancer Invest. 2010. 28: 932– 943. 7 Huh, J. R. and Littman, D. R., Eur. J. Immunol. 2012. 42: 2232–2237.
Full correspondence: Dr. Wen-Ying Zhao, Department of Medical Oncology, Yijishan Hospital, Wannan Medical College, Wuhu, Anhui, 241000, P.R. China Fax: +86-553-3932539 e-mail: [email protected] Received: 4/7/2013 Revised: 10/9/2013 Accepted: 18/9/2013 Accepted article online: 23/10/2013
www.eji-journal.eu
605
