Tumor Biology

, Volume 37, Issue 1, pp 857–863 | Cite as

Prognostic significance of serum ERBB3 and ERBB4 mRNA in lung adenocarcinoma patients

  • Mirza Masroor
  • Jamsheed Javid
  • Rashid Mir
  • Prasant Y
  • Imtiyaz A
  • Mariyam Z
  • Anant Mohan
  • P C Ray
  • Alpana Saxena
Original Article


Serum messenger RNA (mRNA) is an emerging prognostic tool for noninvasive malignant disease prognosis, and to study serum mRNA may have importance in the prognosis and detection of disease. This study aimed to evaluate the possible prognostic role of serum ERBB3 and ERBB4 mRNA expressions in lung adenocarcinoma patients. One hundred newly diagnosed lung adenocarcinoma patients and 100 age- and sex-matched healthy controls were included. Expression was analysed by quantitative real-time PCR and overall survival was analysed by Kaplan–Meier analysis. Serum ERBB3 and ERBB4 mRNA expressions was found to be significantly associated with distant metastases and TNM stages. It was observed that patients with distant metastases had 4.8- and 3.4-fold high ERBB3 and ERBB4 expression in contrast to patients without distant metastases, respectively. It was also found that ERBB3 and ERBB4 mRNA expression was 7.7-fold and 6.7-fold high in TNM stage IV compared to TNM stage I, respectively. Significantly, 2.6-fold increased serum ERBB4 mRNA expression was found in patients with pleural effusion compared to patients without pleural effusion (p = 0.005). Lung adenocarcinoma patients with ≤8- and >8-fold increased serum ERBB3 mRNA expression had 10.0 and 5.5 months of overall median survival while serum ERBB4 mRNA with ≤10- and >10-fold increased expression showed 11.4 and 5.0 months overall median survival, respectively. ERBB3 and ERBB4 together also found to be significantly associated with poor overall median survival. Patients with ≤8 + ≤10- and >8 + >10-fold expression showed 11.3 vs 4.8 months of overall median survival, respectively. In conclusion, serum ERBB3 and ERBB4 mRNA expressions may be a prognostic marker and monitoring of serum ERBB3 and ERBB4 mRNA can be one of the predictive factors for metastases and poor overall survival of lung adenocarcinoma patients.


Lung adenocarcinoma Serum ERBB3 and ERBB4 mRNA Overall survival 



The authors thank to all the study subjects and All India Institute of Medical Sciences, New Delhi, for the assistance in recruiting the subjects.

Conflicts of interest



  1. 1.
    Lo KW, Lo YMD, Leung SF, Tsang YS, Chan LY, Johnson PJ, et al. Analysis of cell-free Epstein-Barr virus associated RNA in the plasma of patients with nasopharyngeal carcinoma. Clin Chem. 1999;45:1292–4.PubMedGoogle Scholar
  2. 2.
    Chen XQ, Bonnefoi H, Pelte MF, Lyautey J, Lederrey C, Movarekhi S, et al. Telomerase RNA as a detection marker in the serum of breast cancer patients. Clin Cancer Res. 2000;6:3823–6.PubMedGoogle Scholar
  3. 3.
    Dasi F, Lledo S, Garcia-Granero E, Ripoll R, Marugan M, Tormo M, et al. Real-time quantification in plasma of human telomerase reverse transcriptase (hTERT) mRNA: a simple blood test to monitor disease in cancer patients. Lab Investig. 2001;81:767–9.CrossRefPubMedGoogle Scholar
  4. 4.
    Ng EK, Tsui NB, Lam NY, Chiu RW, Yu SC, Wong SC, et al. Presence of filterable and nonfilterable mRNA in the plasma of cancer patients and healthy individuals. Clin Chem. 2002;48:1212–7.PubMedGoogle Scholar
  5. 5.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, et al. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.CrossRefPubMedGoogle Scholar
  6. 6.
    Stringer BK, Cooper AG, Shepard SB. Overexpression of the G-protein inwardly rectifying potassium channel 1 (GIRK1) in primary breast carcinomas correlates with axillary lymph node metastasis. Cancer Res. 2001;61:582–8.PubMedGoogle Scholar
  7. 7.
    Baselga J, Swain SM. Novel anticancer targets: revisiting ERBB2 and discovering ERBB3. Nat Rev Cancer. 2009;9:463–75.CrossRefPubMedGoogle Scholar
  8. 8.
    Hynes NE, MacDonald G. ERBB receptors and signaling pathways in cancer. Curr Opin Cell Biol. 2009;21:177–84.CrossRefPubMedGoogle Scholar
  9. 9.
    Olayioye MA, Neve RM, Lane HA, Hynes NE. The ERBB signaling network: receptor heterodimerization in development and cancer. EMBO J. 2000;19:3159–67.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Scheurle D, Jahanzeb M, Aronsohn RS, Watzek L, Narayanan R. HER-2/neu expression in archival non-small cell lung carcinoma using FDA-approved Hercep test. Anticancer Res. 2000;20:2091–8.PubMedGoogle Scholar
  11. 11.
    Kraus MH, Issing W, Miki T, Popescu NC, Aaronson SA. Isolation and characterization of ERBB3, a third member of the ERBB/epidermal growth factor receptor family: evidence for overexpression in a subset of human mammary tumors. Proc Natl Acad Sci U S A. 1989;86:9193–7.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Lee JW, Soung YH, Seo SH, Kim SY, Park CH, Wang YP, et al. Somatic mutations of ERBB2 kinase domain in gastric, colorectal, and breast carcinomas. Clin Cancer Res. 2006;12:57–61.CrossRefPubMedGoogle Scholar
  13. 13.
    Shigematsu H, Gazdar AF. Somatic mutations of epidermal growth factor receptor signaling pathway in lung cancers. Int J Cancer. 2006;118:257–62.CrossRefPubMedGoogle Scholar
  14. 14.
    Memon AA, Sorensen BS, Melgard P, Fokdal L, Thykjaer T, Nexo E. Expression of HER3, HER4 and their ligand heregulin-4 is associated with better survival in bladder cancer patients. Br J Cancer. 2004;91:2034–41.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Lee JC, Wang ST, Chow NH, Yang HB. Investigation of the prognostic value of coexpressed ERBB family members for the survival of colorectal cancer patients after curative surgery. Eur J Cancer. 2002;38:1065–71.CrossRefPubMedGoogle Scholar
  16. 16.
    Bièche I, Onody P, Tozlu S, Driouch K, Vidaud M, Lidereau R. Prognostic value of ERBB family mRNA expression in breast carcinomas. Int J Cancer. 2003;106(5):758–65.CrossRefPubMedGoogle Scholar
  17. 17.
    Xu S, Kitayama J, Yamashita H, Souma D, Nagawa H. Nuclear translocation of HER-4/c-ERBB-4 is significantly correlated with prognosis of esophageal squamous cell carcinoma. J Surg Oncol. 2008;97:44–50.CrossRefPubMedGoogle Scholar
  18. 18.
    Ljuslinder I, Malmer B, Isaksson-Mettävainio M, Oberg A, Henriksson R, Stenling R, et al. ERBB 1–4 expression alterations in primary colorectal cancers and their corresponding metastases. Anticancer Res. 2009;29:1489–94.PubMedGoogle Scholar
  19. 19.
    Rickman OB, Vohra PK, Sanyal B, Vrana JA, Aubry MC, Wigle DA, et al. Analysis of ERBB receptors in pulmonary carcinoid tumors. Clin Cancer Res. 2009;15:3315–24.CrossRefPubMedGoogle Scholar
  20. 20.
    Merimsky O, Staroselsky A, Inbar M, Schwartz Y, Wigler N, Mann A, et al. Correlation between c-ERBB-4 receptor expression and response to gemcitabine-cisplatin chemotherapy in non-small-cell lung cancer. Ann Oncol. 2001;12:1127–31.CrossRefPubMedGoogle Scholar
  21. 21.
    Srinivasan R, Gillett CE, Barnes DM, Gullick WJ. Nuclear expression of the c-ERBB-4/HER-4 growth factor receptor in invasive breast cancers. Cancer Res. 2000;60:1483–7.PubMedGoogle Scholar
  22. 22.
    Gilmour L, Macleod KG, McCaig AGullic WJ, Smyth JF, Langdon SP. Expression of ERBB-4/HER-4 growth factor receptor isoforms in ovarian cancer. Cancer Res. 2001;61:2169–76.PubMedGoogle Scholar
  23. 23.
    Aguilar Z, Akita RW, Finn RS, Ramos BL, Pegram MD, Kabbinavar FF, et al. Biologic effects of heregulin/neu differentiation factor on normal and malignant human breast and ovarian epithelial cells. Oncogene. 1999;18:6050–62.CrossRefPubMedGoogle Scholar
  24. 24.
    Al Moustafa AE, Alaoui-Jamali M, Paterson J, O’Connor-McCourt M. Expression of P185ERBB-2, P160ERBB-3, P180ERBB-4, and heregulin alpha in human normal bronchial epithelial and lung cancer cell lines. Anticancer Res. 1999;19:481–6.PubMedGoogle Scholar
  25. 25.
    Haugen DR, Akslen LA, Varhaug JE, Lillehaug JR. Expression of c-ERBB-3 and c-ERBB-4 proteins in papillary thyroid carcinomas. Cancer Res. 1996;56(6):1184–8.PubMedGoogle Scholar
  26. 26.
    Cohen BD, Siegall CB, Bacus S, Foy L, Green JM, Hellström I, et al. Role of epidermal growth factor receptor family members in growth and differentiation of breast carcinoma. Biochem Soc Symp. 1998;63:199–210.PubMedGoogle Scholar
  27. 27.
    Chomczynski P. A reagent for the single-step simultaneous isolation of RNA, DNA and proteins from cell and tissue samples. Biotechniques. 1993;15:532–7.PubMedGoogle Scholar
  28. 28.
    Ivan B, Peter O, Sengul T, Keltouma D, Michel V, Rosette L, et al. Prognostic value of ERBB family mRNA expression in breast carcinomas. Int J Cancer. 2003;106:758–65.CrossRefGoogle Scholar
  29. 29.
    Kopreski MS, Benko FA, Kwak LW, Gocke CD. Detection of tumor messenger RNA in the serum of patients with malignant melanoma. Clin Cancer Res. 1999;5:1961–5.PubMedGoogle Scholar
  30. 30.
    Fleischhacker M, Beinert T, Ermitsch M, Seferi D, Possinger K, Engelmann C, et al. Detection of amplifiable messenger RNA in the serum of patients with lung cancer. Ann N Y Acad Sci. 2001;945:179–88.CrossRefPubMedGoogle Scholar
  31. 31.
    Friess H, Yamanaka Y, Kobrin MS, Do DA, Buchler MW, Korc M. Enhanced ERBB-3 expression in human pancreatic cancer correlates with tumor progression. Clin Cancer Res. 1995;1:1413–20.PubMedGoogle Scholar
  32. 32.
    Kolb A, Kleeff J, Arnold N, Giese NA, Giese T, Korc M, et al. Expression and differential signaling of heregulins in pancreatic cancer cells. Int J Cancer. 2007;120:514–23.CrossRefPubMedGoogle Scholar
  33. 33.
    Spencer Liles J, Juan Pablo A, Tzeng C-WD, Harrison Howard J, Kossenkov AV, Peter K, et al. ERBB3 expression promotes tumorigenesis in pancreatic adenocarcinoma. Cancer Biol Ther. 2010;10(6):555–63.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Koutsopoulos AV, Mavroudis D, Dambaki KI, Souglakos J, Tzortzaki EG, Drositis J, et al. Simultaneous expression of c-ERBB-1, c-ERBB-2, c-ERBB-3 and c-ERBB-4 receptors in non-small-cell lung carcinomas: correlation with clinical outcome. Lung Cancer. 2007;57:193–200.CrossRefPubMedGoogle Scholar
  35. 35.
    Kawano O, Sasaki H, Endo K, Suzuki E, Haneda H, Yukiue H, et al. ERBB3 mRNA expression correlated with specific clinicopathologic features of Japanese lung cancers. J Surg Res. 2010;146:43–8.CrossRefGoogle Scholar
  36. 36.
    Starr AN, Vexler A, Kerber G, Marmor S, Merimsky O, Ben-Yosef R et al. ERBB-4—a promising tool for prognosis and treatment of non-small cell lung cancer. First IASLC/ASCO international conference: “molecular targeted therapies in lung cancer”. Spain, 2003.Google Scholar
  37. 37.
    Merimsky O, Starr A, Inbar M, Schwartz Y, Wigler N, Mann A, et al. Correlation between c-ERBB-4 receptor expression and response to gemcitabine-cisplatin chemotherapy in non-small-cell lung cancer. Ann Oncol. 2001;12:1127–31.CrossRefPubMedGoogle Scholar
  38. 38.
    Lodge AJ, Anderson JJ, Gullick WJ, Haugk B, Leonard RC, Angus B. Type 1 growth factor receptor expression in node positive breast cancer: adverse prognostic significance of c-ERBB-4. J Clin Pathol. 2003;56(4):300–4.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Pawlowski V, Revillion F, Hebbar M, Hornez L, Peyrat JP. Prognostic value of the type I growth factor receptors in a large series of human primary breast cancers quantified with a real-time reverse transcription-polymerase chain reaction assay. Clin Cancer Res. 2000;6:4217–25.PubMedGoogle Scholar
  40. 40.
    Witton CJ, Reeves JR, Going JJ, Cooke TG, Bartlett JM. Expression of the HER1-4 family of receptor tyrosine kinases in breast cancer. J Pathol. 2003;200:290–7.CrossRefPubMedGoogle Scholar
  41. 41.
    Junttila T, Sundvall M, Lundin M, Lundin J, Tanner M, Härkönen P, et al. Cleavable ERBB4 isoform in estrogen receptor-regulated growth of breast cancer cells. Cancer Res. 2005;65:1384–93.CrossRefPubMedGoogle Scholar
  42. 42.
    Memon AA, Sorensen BS, Melgard P, Fokdal L, Thykjaer T, Nexo E. Expression of HER3, HER4 and their ligand heregulin-4 is associated with better survival in bladder cancer patients. Br J Cancer. 2004;91:2034–41.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Carpenter G. ERBB-4: mechanism of action and biology. Exp Cell Res. 2003;284:66–77.CrossRefPubMedGoogle Scholar
  44. 44.
    Starr A, Greif J, Vexler A, Voghera MA, Gladesh V, Rubin C, et al. ERBB4 increases the proliferation potential of human lung cancer cells and its blockage can be used as a target for anti-cancer therapy. Int J Cancer. 2006;119:269–74.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Mirza Masroor
    • 1
  • Jamsheed Javid
    • 1
  • Rashid Mir
    • 2
  • Prasant Y
    • 1
  • Imtiyaz A
    • 1
  • Mariyam Z
    • 1
  • Anant Mohan
    • 3
  • P C Ray
    • 1
  • Alpana Saxena
    • 1
  1. 1.Department of BiochemistryMaulana Azad Medical College and Associated hospitalsNew DelhiIndia
  2. 2.Faculty of Applied Medical SciencesUniversity of TabukTabukSaudi Arabia
  3. 3.Department of Pulmonary Medicine and Sleep DisorderAll India Institute of Medical SciencesNew DelhiIndia

Personalised recommendations