Vascular endothelial growth factor expression and T-regulatory cells in premenopausal breast cancer

Recchia,Francesco; Candeloro,Giampiero; Necozione,Stefano; Desideri,Giovambattista; Cesta,Alisia; Recchia,Laura; Rea,Silvio

doi:10.3892/ol.2013.1142

Vascular endothelial growth factor expression and T-regulatory cells in premenopausal breast cancer

Authors:
- Francesco Recchia
- Giampiero Candeloro
- Stefano Necozione
- Giovambattista Desideri
- Alisia Cesta
- Laura Recchia
- Silvio Rea
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Affiliations: Department of Oncology, Civilian Hospital, Avezzano, Italy, Department of Internal Medicine and Public Health, University of L'Aquila, L'Aquila, Italy, Department of Health Sciences, University of Molise, Campobasso, Italy, Carlo Ferri Foundation, Monterotondo, Rome, Italy
Published online on: January 18, 2013 https://doi.org/10.3892/ol.2013.1142
Pages: 1117-1122

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Abstract

Estradiol (E2) plays a key role in human reproduction through the induction of vascular endothelial growth factor (VEGF) and T-regulatory cells (T-Regs), which are also important in breast cancer (BC) growth. The primary endpoint of the present study was the investigation of whether E2 suppression, chemotherapy and radiation therapy decreased the levels of VEGF and T-Regs of premenopausal patients with high-risk early BC. The secondary endpoints were toxicity, progression‑free survival (PFS) and overall survival (OS). Between April 2003 and July 2008, 100 premenopausal women with early, high-risk BC were entered into the study. The characteristics of the patients were as follows: median age, 43 years (range, 26-45); median number of positive axillary nodes, 3.3; median Ki-67, 33%. Plasma E2, VEGF and T-Reg were measured at baseline and every year. Treatment comprised luteneizing hormone‑releasing hormone (LH-RH) analogue, tailored chemotherapy, radiation therapy and hormonal therapy in oestrogen receptor-positive (ER+) tumours. At 4 years, a statistically significant decrease in E2, VEGF and T-Reg levels was observed; the PFS and OS rates were 94 and 98%, respectively. Hot flushes and G1 osteopenia occurred following LH-RH analogue administration, while no unexpected toxicity was observed following chemotherapy. E2 deprivation with an LH-RH analogue, tailored chemotherapy, radiation therapy and hormonal therapy in ER+ tumours decreased plasma VEGF levels and T-Regs numbers in premenopausal high-risk ER+ and ER- BC patients. In addition, a favorable impact on PFS and OS was observed.

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1	Yager JD and Davidson NE: Estrogen carcinogenesis in breast cancer. N Engl J Med. 354:270–282. 2006. View Article : Google Scholar : PubMed/NCBI
2	Buteau-Lozano H, Ancelin M, Lardeux B, Milanini J and Perrot-Applanat M: Transcriptional regulation of vascular endothelial growth factor by estradiol and tamoxifen in breast cancer cells: a complex interplay between estrogen receptors alpha and beta. Cancer Res. 62:4977–4984. 2002.
3	Arruvito L, Sanz M, Banham AH and Fainboim L: Expansion of CD4+CD25+ and FOXP3+ regulatory T cells during the follicular phase of the menstrual cycle: implications for human reproduction. J Immunol. 178:2572–2578. 2007.
4	Billingham RE, Brent L and Medawar PB: Actively acquired tolerance of foreign cells. Nature. 172:603–606. 1953. View Article : Google Scholar : PubMed/NCBI
5	Stassen M, Jonuleit H, Müller C, Klein M, Richter C, Bopp T, Schmitt S and Schmitt E: Differential regulatory capacity of CD25+ T regulatory cells and preactivated CD25+ T regulatory cells on development, functional activation, and proliferation of Th2 cells. J Immunol. 173:267–274. 2004.
6	Polanczyk MJ, Carson BD, Subramanian S, Afentoulis M, Vandenbark AA, Ziegler SF and Offner H: Cutting edge: estrogen drives expansion of the CD4+CD25+ regulatory T cell compartment. J Immunol. 173:2227–2230. 2004.PubMed/NCBI
7	Wu Y, Zhong Z, Huber J, Bassi R, Finnerty B, Corcoran E, Li H, Navarro E, Balderes P, Jimenez X, Koo H, Mangalampalli VR, Ludwig DL, Tonra JR and Hicklin DJ: Anti-vascular endothelial growth factor receptor-1 antagonist antibody as a therapeutic agent for cancer. Clin Cancer Res. 12:6573–6584. 2006. View Article : Google Scholar : PubMed/NCBI
8	Yamamoto Y, Toi M, Kondo S, Matsumoto T, Suzuki H, Kitamura M, Tsuruta K, Taniguchi T, Okamoto A, Mori T, Yoshida M, Ikeda T and Tominaga T: Concentrations of vascular endothelial growth factor in the sera of normal controls and cancer patients. Clin Cancer Res. 2:821–826. 1996.PubMed/NCBI
9	Lissoni P, Fugamalli L, Malugani F, Ardizzoia A, Secondino S, Tancini G and Gardani GS: Chemotherapy and angiogenesis in advanced cancer: vascular endothelial growth factor (VEGF) decline as predictor of disease control during Taxol therapy in metastatic breast cancer. Int J Biol Markers. 15:308–311. 2000.
10	Bates GJ, Fox SB, Han C, Leek RD, Garcia JF, Harris AL and Banham AH: Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J Clin Oncol. 24:5373–5380. 2006. View Article : Google Scholar : PubMed/NCBI
11	Recchia F, Saggio G, Amiconi G, Di Blasio A, Cesta A, Candeloro G and Rea S: Gonadotropin-releasing hormone analogues added to adjuvant chemotherapy protect ovarian function and improve clinical outcomes in young women with early breast carcinoma. Cancer. 106:514–523. 2006. View Article : Google Scholar
12	Recchia F, Nuzzo A, Lalli A, De Filippis S and Torchio P: Activity of standard-dose carboplatin, cyclophosphamide, and etoposide in patients with metastatic breast cancer with previous exposure to anthracyclines. Am J Clin Oncol. 20:166–168. 1997. View Article : Google Scholar : PubMed/NCBI
13	Recchia F, De Fillipis S, Piccinini M and Rea S: High-dose carboplatin, cyclophosphamide, etoposide with hematological growth factors, without stem cell support in patients with advanced cancer. Anticancer Res. 23:4141–4147. 2003.PubMed/NCBI
14	Recchia F, Saggio G, Cesta A, Alesse E, Gallo R, Necozione S and Rea S: Phase II randomized study of interleukin-2 with or without 13-cis retinoic acid as maintenance therapy in patients with advanced cancer responsive to chemotherapy. Anticancer Res. 25:3149–3157. 2005.PubMed/NCBI
15	Simon R: Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 10:1–10. 1989. View Article : Google Scholar : PubMed/NCBI
16	Kaplan EL and Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc. 53:457–481. 1958. View Article : Google Scholar
17	Brenner H and Hakulinen T: Are patients diagnosed with breast cancer before age 50 years ever cured? J Clin Oncol. 22:432–438. 2004.PubMed/NCBI
18	Beatson GT: On the treatment of inoperable cases of carcinoma of the mamma: suggestions for a new method of treatment with illustrative cases. Lancet. ii:104–107. 1896. View Article : Google Scholar
19	No authors listed:. Systematic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Early Breast Cancer Trialists’ Collaborative Group Lancet. 339:1–15. 1992.
20	Goel S, Sharma R, Hamilton A and Beith J: LHRH agonists for adjuvant therapy of early breast cancer in premenopausal women. Cochrane Database Syst Rev. 4:CD0045622009.
21	Early Breast Cancer Trialists’ Cooperative Group (EBCTCG): Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 365:1687–1717. 2005.PubMed/NCBI
22	Eliassen AH, Missmer SA, Tworoger SS, Spiegelman D, Barbieri RL, Dowsett M and Hankinson SE: Endogenous steroid hormone concentrations and risk of breast cancer among premenopausal women. J Natl Cancer Inst. 98:1406–1415. 2006. View Article : Google Scholar : PubMed/NCBI
23	Anders CK, Hsu DS, Broadwater G, Acharya CR, Foekens JA, Zhang Y, Wang Y, Marcom PK, Marks JR, Febbo PG, Nevins JR, Potti A and Blackwell KL: Young age at diagnosis correlates with worse prognosis and defines a subset of breast cancers with shared patterns of gene expression. J Clin Oncol. 26:3324–3330. 2008. View Article : Google Scholar : PubMed/NCBI
24	Elkin M, Orgel A and Kleinman HK: An angiogenic switch in breast cancer involves estrogen and soluble vascular endothelial growth factor receptor 1. J Natl Cancer Inst. 96:875–878. 2004. View Article : Google Scholar : PubMed/NCBI
25	De Laurentiis M, Cancello G, D’Agostino D, Giuliano M, Giordano A, Montagna E, Lauria R, Forestieri V, Esposito A, Silvestro L, Pennacchio R, Criscitiello C, Montanino A, Limite G, Bianco AR and De Placido S: Taxane-based combinations as adjuvant chemotherapy of early breast cancer: a meta-analysis of randomized trials. J Clin Oncol. 26:44–53. 2008.PubMed/NCBI
26	Toledano A, Azria D, Garaud P, Fourquet A, Serin D, Bosset JF, Miny-Buffet J, Favre A, Le Floch O and Calais G: Phase III trial of concurrent or sequential adjuvant chemoradiotherapy after conservative surgery for early-stage breast cancer: final results of the ARCOSEIN trial. J Clin Oncol. 25:405–410. 2007. View Article : Google Scholar
27	Detre S, Salter J, Barnes DM, Riddler S, Hills M, Johnston SR, Gillett C, A’Hern R and Dowsett M: Time-related effects of estrogen withdrawal on proliferation- and cell death-related events in MCF-7 xenografts. Int J Cancer. 81:309–313. 1999. View Article : Google Scholar : PubMed/NCBI
28	Linderholm B, Grankvist K, Wilking N, Johansson M, Tavelin B and 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. 18:1423–1431. 2000.
29	Nakamura Y, Yasuoka H, Tsujimoto M, Yang Q, Imabun S, Nakahara M, Nakao K, Nakamura M, Mori I and Kakudo K: Prognostic significance of vascular endothelial growth factor D in breast carcinoma with long-term follow-up. Clin Cancer Res. 9:716–721. 2003.PubMed/NCBI
30	Eppenberger U, Kueng W, Schlaeppi JM, Roesel JL, Benz C, Mueller H, Matter A, Zuber M, Luescher K, Litschgi M, Schmitt M, Foekens JA and Eppenberger-Castori S: Markers of tumour angiogenesis and proteolysis independently define high- and low-risk subsets of node-negative breast cancer patients. J Clin Oncol. 16:3129–3136. 1998.PubMed/NCBI
31	Salven P, Mänpää H, Orpana A, Alitalo K and Joensuu H: Serum vascular endothelial growth factor is often elevated in disseminated cancer. Clin Cancer Res. 5:647–651. 1997.PubMed/NCBI
32	Gabrilovich DI, Chen HL, Girgis KR, Cunnigham HT, Meny GM, Nadaf S, Kavanaugh D and Carbone DP: Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dentritic cells. Nat Med. 2:1096–1103. 1996. View Article : Google Scholar : PubMed/NCBI
33	Pidgeon GP, Barr MP, Harmey JH, Foley DA and Bouchier-Hayes DJ: Vascular endothelial growth factor (VEGF) upregulates BCL-2 and inhibits apoptosis in human and murine mammary adenocarcinoma cells. Br J Cancer. 85:273–278. 2001. View Article : Google Scholar : PubMed/NCBI
34	Merlo A, Casalini P, Carcangiu ML, Malventano C, Triulzi T, Mènard S, Tagliabue E and Balsari A: FOXP3 expression and overall survival in breast cancer. J Clin Oncol. 27:1746–1752. 2009. View Article : Google Scholar : PubMed/NCBI
35	Gupta S, Joshi K, Wig JD and Arora SK: Intratumoral FOXP3 expression in infiltrating breast carcinoma: Its association with clinicopathologic parameters and angiogenesis. Acta Oncol. 46:792–797. 2007. View Article : Google Scholar : PubMed/NCBI
36	Decker T, Fischer G, Bücke W, Bücke P, Stotz F, Grüneberger A, Gropp-Meier M, Wiedemann G, Pfeiffer C, Peschel C and Götze K: Increased number of regulatory T cells (T-regs) in the peripheral blood of patients with Her-2/neu-positive early breast cancer. J Cancer Res Clin Oncol. 138:1945–1950. 2012. View Article : Google Scholar : PubMed/NCBI
37	Jonat W, Kaufmann M, Sauerbrei W, Blamey R, Cuzick J, Namer M, Fogelman I, de Haes JC, de Matteis A, Stewart A, Eiermann W, Szakolczai I, Palmer M, Schumacher M, Geberth M and Lisboa B; Zoladex Early Breast Cancer Research Association Study: Goserelin versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy in premenopausal patients with node-positive breast cancer: The Zoladex Early Breast Cancer Research Association Study. J Clin Oncol. 20:4628–4635. 2002. View Article : Google Scholar
38	Swain SM, Jeong JH, Geyer CE Jr, Costantino JP, Pajon ER, Fehrenbacher L, Atkins JN, Polikoff J, Vogel VG, Erban JK, Rastogi P, Livingston RB, Perez EA, Mamounas EP, Land SR, Ganz PA and Wolmark N: Longer therapy, iatrogenic amenorrhea, and survival in early breast cancer. N Engl J Med. 362:2053–2065. 2010. View Article : Google Scholar : PubMed/NCBI
39	Park IH, Han HS, Lee H, Lee KS, Kang HS, Lee S, Kim SW, Jung S and Ro J: Resumption or persistence of menstruation after cytotoxic chemotherapy is a prognostic factor for poor disease-free survival in premenopausal patients with early breast cancer. Ann Oncol. 23:2283–2289. 2012. View Article : Google Scholar : PubMed/NCBI