HER-2/neu overexpression correlates with increased expression of VEGF in primary breast carcinoma
Background: Overexpression of HER-2/neu is associated with up-regulation of vascular endothelial growth factor (VEGF) in human breast cancer cells in vitro. Preclinical experiments indicate that increased expression of VEGF may in part mediate the biologically aggressive phenotype of HER-2/neu overexpressing human breast cancer. It was the purpose of this study to: (a) evaluate the association between HER-2/neu and VEGF expression in a cohort of primary breast cancer patients; (b) find out any association of HER-2/neu or VEGF with traditional histologic prognostic parameters.
Materials and Methods: HER-2/neu and VEGF were measured by immunohistochemistry in 70 cases of newly diagnosed primary breast cancers and the relation between these two markers and their relations with traditional prognostic factors were analyzed by statistical methods.
Results: Our findings indicate a significant positive association between HER-2/neu and VEGF expression. VEGF did not show significant association with tumor size, histologic grade or lymph node status. HER-2/neu overexpression was maximum in grade II, followed by grade I and III with a significant p value (<0.001). But HER-2/neu didn’t have any association with tumor size or lymph node status.
Conclusion: The positive association between HER-2/neu and VEGF expression implicates VEGF in the aggressive phenotype exhibited by HER-2/neu overexpression, and supports the use of combination therapies directed against both HER-2/neu and VEGF for treatment of breast cancers that overexpress HER-2/neu. The unusual association found between HER-2/neu and grade of tumor may be due to uneven distribution of cases among different grades of tumor.
Salceda S, Caro J. Hypoxia-inducible factor 1alpha (HIF-1alpha) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox-induced changes. J Biol Chem.1997 Sep 5;272(36):22642-47.
Rosai J. Breast. In: Chan JKC, Arber DA, Brunning RD, Desmet VJ, Demasters BKK, Ordonez NG, Rosenblum MK, Tallini G, editors. Rosai and Ackerman's Surgical Pathology. 10th ed. St. Louis: Elsevier; 2011.p1659-1770.
Makroo RN, Chowdhry M, Kumar M, Srivastava P, Tyagi R, Bhadauria P, Kaul S, Sarin R, Das PK, Dua H. Correlation between HER2 gene amplification and protein overexpression through fluorescence in situ hybridization and immunohistochemistry in breast carcinoma patients. Indian J Pathol Microbiol. 2012 Oct-Dec;55(4):481-84. Doi: http://www.ijpmonline.org/text.asp?2012/55/4/481/107785.
Xie K, Wei D, Shi Q, Huang S. Constitutive and inducible expression and regulation of vascular endothelial growth factor. Cytokine & Growth Factor Reviews. 2004; 15(5): 297–324. DOI: https://doi.org/10.1016/j.cytogfr.2004.04.003.
Schneider BP, Miller KD. Angiogenesis of Breast Cancer. J Clin Oncol. 2005 March 10; 23(8):1782-90.
Maae, E, Nielsen M, Steffensen KD, Jakobsen EH, Jakobsen A, Sørensen FB. Estimation of Immunohistochemical Expression of VEGF in Ductal Carcinomas of the Breast. J Histochem Cytochem. 2011 Aug; 59(8):750 –760. doi: https://doi.org/10.1369%2F0022155411412599.
Weigand M, Hantel P, Kreienberg R, Waltenberger J. Autocrine vascular endothelial growth factor signaling in breast cancer: Evidence from cell lines and primary breast cancer cultures in vitro. Angiogenesis. 2005;8(3):197-204. Epub 2005 Nov 19.
Linderholm B, Grankvist K, Wilking N, Johansson M, Tavelin B, Henriksson R. Correlation of Vascular Endothelial Growth Factor Content With Recurrences, Survival, and First Relapse Site in Primary Node-positive Breast Carcinoma After Adjuvant Treatment. J Clin Oncol. 2000 (April) 18(7): 1423-31.
Gasparini G, Toi M, Miceli R, Vermeulen PB, Dittadi R, Biganzoli E, Morabito A, Fanelli M, Gatti C, Suzuki H, Tominaga T, Dirix LY, Gion M. Clinical relevance of vascular endothelial growth factor and thymidine phosphorylase in patients with node-positive breast cancer treated with either adjuvant chemotherapy or hormone therapy. Cancer J Sci Am. 1999 Mar-Apr;5(2):101-11.
Foekens JA, Peters HA, Grebenchtchikov N, Look MP, Meijer-van Gelder ME, Geurts-Moespot A, van der Kwast TH, Sweep CG, Klijn JG. High tumor levels of vascular endothelial growth factor predict poor response to systemic therapy in advanced breast cancer. Cancer Res. 2001 Jul 15;61(14):5407-14.
Petit AM, Rak J, Hung MC, Rockwell P, Goldstein N, Fendly B, Kerbel RS. Neutralizing antibodies against epidermal growth factor and ErbB-2/neu receptor tyrosine kinases down-regulate vascular endothelial growth factor production by tumor cells in vitro and in vivo: angiogenic implications for signal transduction therapy of solid tumors. Am J Pathol. 1997 Dec;151(6):1523-30.
Laughner E, Taghavi P, Chiles K, Mahon PC, Semenza GL. HER2 (neu) Signaling Increases the Rate of Hypoxia-Inducible Factor 1α (HIF-1α) Synthesis: Novel Mechanism for HIF-1 Mediated Vascular Endothelial Growth Factor Expression. Mol Cell Biol. 2001(June); 21(12):3995–4004. DOI: https://doi.org/10.1128/MCB.21.12.3995-4004.2001.
Xiong S, Grijalva R, Zhang L, Nguyen NT, Pisters PW, Pollock RE, Yu D. Up regulation of vascular endothelial growth factor in breast cancer cells by heregulin-beta1-activated P38 signaling pathway enhances endothelial cell migration. Cancer Res. 2001 Feb 15;61(4):1727-32.
Yang W, Klos K, Yang Y, Smith TL, Shi D, Yu D. ErbB2 over expression correlates with increased expression of vascular endothelial growth factors A, C, and D in human breast carcinoma. Cancer. 2002 Jun 1;94(11):2855-61.
Konecny GE, Meng YG, Untch M, Wang HJ, Bauerfeind I, Epstein M, Stieber P, Vernes JM, Gutierrez J, Hong K, Beryt M, Hepp H, Slamon DJ, Pegram MD. Association between HER-2/neu and Vascular Endothelial Growth Factor Expression Predicts Clinical Outcome in Primary Breast Cancer Patients. Clin Cancer Res. 2004 March 1; 10(5):1706-16.
Linderholm B, Andersson J, Lindh B, Beckman L, Erlanson M, Edin K, Tavelin B, Grankvist K, Henriksson R. Overexpression of c-erbB-2 is related to a higher expression of vascular endothelial growth factor (VEGF) and constitutes an independent prognostic factor in primary node-positive breast cancer after adjuvant systemic treatment. Eur J Cancer. 2004 Jan;40(1):33-42.
Qiao EQ, Ji M, Wu J, Li J, Xu X, Ma R, Zhang X, He Y, Zha Q, Song X, Zhu L, Tang JH. Joint detection of multiple immunohistochemical indices and clinical significance in breast cancer. Mol Clin Oncol. 2013 Jul;1(4):703-10. Epub 2013 May 8.
Foy KC, Liu Z, Phillips G, Miller M, Kaumaya PT. Combination Treatment with HER-2 and VEGF Peptide Mimics Induces Potent Anti-tumor and Anti-angiogenic Responses in Vitro and in Vivo. J Biol Chem. 2011 Apr 15;286(15):13626-37. doi: https://doi.org/10.1074/jbc.M110.216820. Epub 2011 Feb 16.
Baker H: 2013 San Antonio Breast Cancer Symposium. Lancet Oncol. 2014 Feb; 15(2):138.
Königsberg R, Maierhofer J, Steininger T, Kienzer G, Dittrich C. Long-term remission of a Her2/neu positive primary breast cancer under double monoclonal antibody therapy with trastuzumab and bevacizumab. Radiol Oncol. 2014 Apr 25;48(2):184-88. doi: https://doi.org/10.2478/raon-2013-0083.
Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, Allred DC, Bartlett JMS, Bilous M, Fitzgibbons P, Hanna W, Jenkins RB, Mangu PB, Paik S, Perez EA, Press MF, Spears PA, Vance GH, Viale G, Hayes DF, American Society of Clinical Oncology, College of American Pathologists. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol. 2013 Nov 1;31(31):3997-4013. doi: https://doi.org/10.1200/JCO.2013.50.9984. Epub 2013 Oct 7.A
El-Gendi S, Abdel-Hadi M. Lymphatic vessel density as prognostic factor in breast carcinoma: relation to clinicopathologic parameters. J Egypt Natl Canc Inst. 2009 Jun;21(2):139-49.
Hirata BKB, Oda JMM, Guembarovski RL, Ariza CB, Coral de Oliveira CE, Watanabe MAE. Molecular Markers for Breast Cancer: Prediction on Tumor Behavior. Hindawi Publishing Corporation. Hindawi Publishing Corporation. Disease Markers Volume 2014, Article ID 513158, 12 pages http://dx.doi.org/10.1155/2014/513158
Mills SE. The Breast. In:Carter D, Schnitt SJ, Mills RR, editors. Stenberg’s Diagnostic Surgical Pathology. 5th ed. Baltimore, Philadelphia: Lippincott Williams & Wilkins; 2010; p285-350.
Ye X, Lu D. HER2 and VEGF expression in breast cancer and their correlations. Chin.-Ger. J. Clin. Oncol. 2010 April; 9(4):208–12. doi: https://doi.org/10.1007/s10330-010-0018-6.
Esraa A. Dujaily AL, Al-Kelabi LH, Alkhafaji AJN, Al-Harris ESM. HER-2/neu overexpression in correlation to Vascular Endothelial Growth Factor, grade and stage of Non other wised specified Invasive ductal carcinoma. Al-Qadisiah Medical Journal. 2010; 6(10): 27-37.
Semenza, GL. HIF-1: Using two Hands to Flip the Angiogenic Switch. Cancer Metastasis Rev. 2000 June;19(1-2):59-65. doi: https://doi.org/10.1023/A:1026544214667.
Blackwell KL, Dewhirst MW, Liotcheva V, Snyder S, Broadwater G, Bentley R, Lal A, Riggins G, Anderson S, Vredenburgh J, Proia A, Harris LN. HER-2 gene amplification correlates with higher levels of angiogenesis and lower levels of hypoxia in primary breast tumors. Clin Cancer Res. 2004 Jun 15;10(12 Pt 1):4083-88.