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Medical Oncology

, Volume 29, Issue 4, pp 2640–2648 | Cite as

Estrogen upregulates the IGF-1 signaling pathway in lung cancer through estrogen receptor-β

  • Hexiao Tang
  • Yongde LiaoEmail author
  • Guang Chen
  • Liqiang Xu
  • Chao Zhang
  • Sheng Ju
  • Sheng Zhou
Original Paper

Abstract

The estrogen receptor (ER) signaling and the insulin-like growth factor-1 receptor (IGF-1R) signaling are implicated in lung cancer progression. Here, we sought to investigate whether estrogen regulated the IGF-1R signaling in non-small cell lung cancer (NSCLC) and the underlying mechanisms. We examined and analyzed the correlation of the expression of aromatase (Arom), ERβ, ERα, insulin-like growth factor-1 (IGF-1), and IGF-1R in NSCLC. Tissue-microarray and immunohistochemistry analysis of tissue specimens from 162 NSCLC patients and 38 patients with benign pulmonary lesions showed that Arom, ERβ, IGF-1, and IGF-1R were overexpressed while ERα was not expressed in NSCLC. Furthermore, ERβ expression was positively correlated with that of Arom, IGF-1, and IGF-1R (r = 0.554, 0.649, 0.496, respectively, P values are equal to 0.000), while Arom expression was positively associated with that of IGF-1 and IGF-1R (r = 0.657, 0.714, respectively, P values are equal to 0.000). Additionally, ERβ, IGF-1, and phospho-IGF-1R, but not ERα, were expressed in A549 cells. Immunoblotting assays showed that A549 cells treated with E2 showed significantly higher IGF-1 and p-IGF-1R levels than those receiving the combination treatment of 17β-estradiol (E2) and fulvestrant (Ful, ER antagonist) (P = 0.042, 0.002, respectively) or controls (P values are equal to 0.000). The MTT assays further revealed that E2 and IGF-1 synergistically promoted A549 cell proliferation. Together, our study provides the first direct evidence for an interaction between ER and IGF-1R in lung cancer. We showed that estrogen upregulated the IGF-1R signaling through ERβ in lung cancer tissues and A549 cells. These findings shed further light on the mechanisms whereby estrogen promotes lung cancer and highlight the ER and IGF-1R signaling pathways as promising targets for combinational therapy for lung cancer.

Keywords

Non-small cell lung cancer Estrogen receptor β Insulin-like growth factor-1 receptor A549 cells Tissue-microarray immunohistochemistry 

Abbreviations

Arom

Aromatase

ER

Estrogen receptor

IGF-1

Insulin-like growth factor-1

IGF-1R

Insulin-like growth factor-1 receptor

NSCLC

Non-small cell lung cancer

BPL

Benign pulmonary lesions

TMA

Tissue-microarray

IHC

Immunohistochemistry

E2

17β-estradiol

Ful

Fulvestrant

Notes

Acknowledgments

This study was founded by Science and Technology Activity Foundation of Returned Overseas Scholars (Human Resources and Social Security Department of Hubei Province [2008]86, China). The authors thank Research Center of Experimental Medicine for laboratory equipment services and Department of Statistics for the statistical calculations of this study, both coming from Tongji Medical College, Huazhong University of Science and Technology (Wuhan, China).

Conflict of interest

No potential conflicts of interest were disclosed.

References

  1. 1.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90. doi: 10.3322/caac.20107.PubMedCrossRefGoogle Scholar
  2. 2.
    Yang GH, Wang JF, Wan X, Wang LJ, Chen AP. Quantitative analysis of factors affected mortality trend in Chinese, 2002. Zhonghua Liu Xing Bing Xue Za Zhi. 2005;26(12):934–8.PubMedGoogle Scholar
  3. 3.
    Stabile LP, Siegfried JM. Estrogen receptor pathways in lung cancer. Curr Oncol Rep. 2004;6(4):259–67.PubMedCrossRefGoogle Scholar
  4. 4.
    Zhang G, Liu X, Farkas AM, Parwani AV, Lathrop KL, Lenzner D, et al. Estrogen receptor beta functions through nongenomic mechanisms in lung cancer cells. Mol Endocrinol. 2009;23(2):146–56. doi: 10.1210/me.2008-0431.PubMedCrossRefGoogle Scholar
  5. 5.
    Fagan DH, Yee D. Crosstalk between IGF1R and estrogen receptor signaling in breast cancer. J Mammary Gland Biol Neoplasia. 2008;13(4):423–9. doi: 10.1007/s10911-008-9098-0.PubMedCrossRefGoogle Scholar
  6. 6.
    Boccardo F, Rubagotti A, Battaglia M, Zattoni F, Bertaccini A, Romagnoli A, et al. Influence of bicalutamide with or without tamoxifen or anastrozole on insulin-like growth factor 1 and binding proteins in prostate cancer patients. Int J Biol Markers. 2006;21(2):123–6.PubMedGoogle Scholar
  7. 7.
    Kanagaraj P, Vijayababu MR, Ilangovan R, Senthilkumar K, Venkataraman P, Aruldhas MM, et al. Effect of 17beta-estradiol on apoptosis, IGF system components and gelatinases A and B in prostate cancer cells (PC-3). Clin Chim Acta. 2007;377(1–2):70–8. doi: 10.1016/j.cca.2006.07.030.PubMedCrossRefGoogle Scholar
  8. 8.
    Maki RG. Small is beautiful: insulin-like growth factors and their role in growth, development, and cancer. J Clin Oncol. 2010;28(33):4985–95. doi: 10.1200/JCO.2009.27.5040.PubMedCrossRefGoogle Scholar
  9. 9.
    Samani AA, Yakar S, LeRoith D, Brodt P. The role of the IGF system in cancer growth and metastasis: overview and recent insights. Endocr Rev. 2007;28(1):20–47. doi: 10.1210/er.2006-0001.PubMedCrossRefGoogle Scholar
  10. 10.
    Liao Y, Abel U, Grobholz R, Hermani A, Trojan L, Angel P, et al. Up-regulation of insulin-like growth factor axis components in human primary prostate cancer correlates with tumor grade. Hum Pathol. 2005;36(11):1186–96. doi: 10.1016/j.humpath.2005.07.023.PubMedCrossRefGoogle Scholar
  11. 11.
    Liao YD, Zhao JP, Zhou S, Fu SL, Wan YQ, Doris M. The correlation between IGF1, IGF2 expression and lymph node metastasis in non-small cell lung cancer [in Chinese]. Cancer Res Prev Treat. 2006;33(12):868–71.Google Scholar
  12. 12.
    Liao YD, Zhou S, Zhao JP, Yuan YH, Huang Q, Doris M. Expression and significance of IGF1, IGF1R and AKT, the components of IGF signaling pathway, in primary adenocarcinoma of the lung. [in Chinese]. J Pract Oncol. 2006;21(1):15–9.Google Scholar
  13. 13.
    Dziadziuszko R, Camidge DR, Hirsch FR. The insulin-like growth factor pathway in lung cancer. J Thorac Oncol. 2008;3(8):815–8. doi: 10.1097/JTO.0b013e31818180f5.PubMedCrossRefGoogle Scholar
  14. 14.
    Ryan PD, Goss PE. The emerging role of the insulin-like growth factor pathway as a therapeutic target in cancer. Oncologist. 2008;13(1):16–24. doi: 10.1634/theoncologist.2007-0199.PubMedCrossRefGoogle Scholar
  15. 15.
    Bogazzi F, Raggi F, Ultimieri F, Russo D, D’Alessio A, Manariti A, et al. Regulation of cardiac fatty acids metabolism in transgenic mice overexpressing bovine GH. J Endocrinol. 2009;201(3):419–27. doi: 10.1677/JOE-08-0194.PubMedCrossRefGoogle Scholar
  16. 16.
    Schon J, Neumann S, Wildt DE, Pukazhenthi BS, Jewgenow K. Localization of oestrogen receptors in the epididymis during sexual maturation of the domestic cat. Reprod Domest Anim. 2009;44(Suppl 2):294–301. doi: 10.1111/j.1439-0531.2009.01391.x.PubMedCrossRefGoogle Scholar
  17. 17.
    Klein C, Scoggin KE, Ealy AD, Troedsson MH. Transcriptional profiling of equine endometrium during the time of maternal recognition of pregnancy. Biol Reprod. 2010;83(1):102–13. doi: 10.1095/biolreprod.109.081612.PubMedCrossRefGoogle Scholar
  18. 18.
    Galic S, Klingler-Hoffmann M, Fodero-Tavoletti MT, Puryer MA, Meng TC, Tonks NK, et al. Regulation of insulin receptor signaling by the protein tyrosine phosphatase TCPTP. Mol Cell Biol. 2003;23(6):2096–108.PubMedCrossRefGoogle Scholar
  19. 19.
    Augustine-Rauch KA, Zhang Q, Kleinman M, Lawton R, Welsh MJ. A study of vehicles for dosing rodent whole embryo culture with non aqueous soluble compounds. Reprod Toxicol. 2004;18(3):391–8. doi: 10.1016/j.reprotox.2004.01.006.PubMedCrossRefGoogle Scholar
  20. 20.
    Kang KF, Wang XW, Chen XW, Shi XC. Expression and clinical significance of Beclin1 and NF-κB p65 protein in primary human hepatocellular carcinoma. [in Chinese]. World Chin J Digestol. 2008;16(20):2244–7.Google Scholar
  21. 21.
    Yang XR, Pfeiffer RM, Garcia-Closas M, Rimm DL, Lissowska J, Brinton LA, et al. Hormonal markers in breast cancer: coexpression, relationship with pathologic characteristics, and risk factor associations in a population-based study. Cancer Res. 2007;67(21):10608–17. doi: 10.1158/0008-5472.CAN-07-2142.PubMedCrossRefGoogle Scholar
  22. 22.
    Marquez DC, Lee J, Lin T, Pietras RJ. Epidermal growth factor receptor and tyrosine phosphorylation of estrogen receptor. Endocrine. 2001;16(2):73–81. doi: 10.1385/ENDO:16:2:073.PubMedCrossRefGoogle Scholar
  23. 23.
    Marquez DC, Pietras RJ. Membrane-associated binding sites for estrogen contribute to growth regulation of human breast cancer cells. Oncogene. 2001;20(39):5420–30. doi: 10.1038/sj.onc.1204729.PubMedCrossRefGoogle Scholar
  24. 24.
    Sunwoo H, Gujral N, Suresh M. Competitive and double antibody sandwich ELISA for the quantification of lactoferrins by using monoclonal and chicken egg yolk IgY antibodies. J Immunoassay Immunochem. 2011;32(2):79–92. doi: 10.1080/15321819.2010.543218.PubMedCrossRefGoogle Scholar
  25. 25.
    Tkaczuk KH, Tait NS, Ioffe O, Tan M, Goloubeva OG, Lesko SA, et al. Computer assisted quantitative immunofluorescence of tumor tissue marker expression and clinical outcome to chemotherapy in advanced breast cancer patients. Discov Med. 2011;12(62):33–40.PubMedGoogle Scholar
  26. 26.
    Chang MM, Lovett J. A laboratory exercise illustrating the sensitivity and specificity of Western blot analysis. Biochem Mol Biol Educ. 2011;39(4):291–7. doi: 10.1002/bmb.20501.PubMedCrossRefGoogle Scholar
  27. 27.
    McCance KL, Jones RE. Estrogen and insulin crosstalk: breast cancer risk implications. Nurse Pract. 2003;28(5):12–23; quiz 4–5.Google Scholar
  28. 28.
    Weinberg OK, Marquez-Garban DC, Fishbein MC, Goodglick L, Garban HJ, Dubinett SM, et al. Aromatase inhibitors in human lung cancer therapy. Cancer Res. 2005;65(24):11287–91. doi: 10.1158/0008-5472.CAN-05-2737.PubMedCrossRefGoogle Scholar
  29. 29.
    Niikawa H, Suzuki T, Miki Y, Suzuki S, Nagasaki S, Akahira J, et al. Intratumoral estrogens and estrogen receptors in human non-small cell lung carcinoma. Clin Cancer Res. 2008;14(14):4417–26. doi: 10.1158/1078-0432.CCR-07-1950.PubMedCrossRefGoogle Scholar
  30. 30.
    Hershberger PA, Stabile LP, Kanterewicz B, Rothstein ME, Gubish CT, Land S, et al. Estrogen receptor beta (ERbeta) subtype-specific ligands increase transcription, p44/p42 mitogen activated protein kinase (MAPK) activation and growth in human non-small cell lung cancer cells. J Steroid Biochem Mol Biol. 2009;116(1–2):102–9. doi: 10.1016/j.jsbmb.2009.05.004.PubMedCrossRefGoogle Scholar
  31. 31.
    Zhao G, Zhao S, Wang T, Zhang S, Lu K, Yu L, et al. Estrogen receptor beta signaling regulates the progression of Chinese non-small cell lung cancer. J Steroid Biochem Mol Biol. 2011;124(1–2):47–57. doi: 10.1016/j.jsbmb.2011.01.006.PubMedCrossRefGoogle Scholar
  32. 32.
    Miki Y, Suzuki T, Abe K, Suzuki S, Niikawa H, Iida S, et al. Intratumoral localization of aromatase and interaction between stromal and parenchymal cells in the non-small cell lung carcinoma microenvironment. Cancer Res. 2010;70(16):6659–69. doi: 10.1158/0008-5472.CAN-09-4653.PubMedCrossRefGoogle Scholar
  33. 33.
    Lindblad M, Garcia RL, Chandanos E, Lagergren J. Hormone replacement therapy and risks of oesophageal and gastric adenocarcinomas. Br J Cancer. 2006;94(1):136–41. doi: 10.1038/sj.bjc.6602906.PubMedCrossRefGoogle Scholar
  34. 34.
    Mollerup S, Jorgensen K, Berge G, Haugen A. Expression of estrogen receptors alpha and beta in human lung tissue and cell lines. Lung Cancer. 2002;37(2):153–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Hershberger PA, Vasquez AC, Kanterewicz B, Land S, Siegfried JM, Nichols M. Regulation of endogenous gene expression in human non-small cell lung cancer cells by estrogen receptor ligands. Cancer Res. 2005;65(4):1598–605. doi: 10.1158/0008-5472.can-04-2694.PubMedCrossRefGoogle Scholar
  36. 36.
    Schwartz AG, Prysak GM, Murphy V, Lonardo F, Pass H, Schwartz J, et al. Nuclear estrogen receptor beta in lung cancer: expression and survival differences by sex. Clin Cancer Res. 2005;11(20):7280–7. doi: 10.1158/1078-0432.CCR-05-0498.PubMedCrossRefGoogle Scholar
  37. 37.
    Ali G, Donati V, Loggini B, Servadio A, Dell’Omodarme M, Prati MC, et al. Different estrogen receptor beta expression in distinct histologic subtypes of lung adenocarcinoma. Hum Pathol. 2008;39(10):1465–73. doi: 10.1016/j.humpath.2008.02.011.PubMedCrossRefGoogle Scholar
  38. 38.
    Hammoud Z, Tan B, Badve S, Bigsby RM. Estrogen promotes tumor progression in a genetically defined mouse model of lung adenocarcinoma. Endocr Relat Cancer. 2008;15(2):475–83. doi: 10.1677/ERC-08-0002.PubMedCrossRefGoogle Scholar
  39. 39.
    Skov BG, Fischer BM, Pappot H. Oestrogen receptor beta over expression in males with non-small cell lung cancer is associated with better survival. Lung Cancer. 2008;59(1):88–94. doi: 10.1016/j.lungcan.2007.07.025.PubMedCrossRefGoogle Scholar
  40. 40.
    Kawai H, Ishii A, Washiya K, Konno T, Kon H, Yamaya C, et al. Estrogen receptor alpha and beta are prognostic factors in non-small cell lung cancer. Clin Cancer Res. 2005;11(14):5084–9. doi: 10.1158/1078-0432.ccr-05-0200.PubMedCrossRefGoogle Scholar
  41. 41.
    Wu CT, Chang YL, Shih JY, Lee YC. The significance of estrogen receptor beta in 301 surgically treated non-small cell lung cancers. J Thorac Cardiovasc Surg. 2005;130(4):979–86. doi: 10.1016/j.jtcvs.2005.06.012.PubMedCrossRefGoogle Scholar
  42. 42.
    Carmona-Bayonas A. Potential benefit of maintenance trastuzumab and anastrozole therapy in male advanced breast cancer. Breast. 2007;16(3):323–5. doi: 10.1016/j.breast.2006.12.010.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Hexiao Tang
    • 1
  • Yongde Liao
    • 1
    Email author
  • Guang Chen
    • 1
  • Liqiang Xu
    • 1
    • 2
  • Chao Zhang
    • 1
    • 3
  • Sheng Ju
    • 1
    • 4
  • Sheng Zhou
    • 5
  1. 1.Department of Thoracic Surgery, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
  2. 2.Department of Thoracic Surgery, Taihe HospitalHubei University of MedicineShiyanChina
  3. 3.Department of Thoracic SurgeryThe Central Hospital of WuhanWuhanChina
  4. 4.Department of Thoracic SurgeryZhejiang HospitalHangzhouChina
  5. 5.Department of Pathology, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina

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