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. 1999 Sep;81(2):225–231. doi: 10.1038/sj.bjc.6690681

Vascular endothelial growth factor A (VEGF-A) mRNA expression levels decrease after menopause in normal breast tissue but not in breast cancer lesions

R R Greb 1, I Maier 1, D Wallwiener 1, L Kiesel 1
PMCID: PMC2362877  PMID: 10496346

Abstract

We hypothesized that the regulation of microvascular functions and angiogenesis in breast tissue, a well known target of ovarian steroid action, is dependent on the hormonal exposure of the breast. Relative expression levels of VEGF-A (vascular endothelial growth factor A), a putative key regulator of angiogenesis in breast cancer, were analysed in the tumour and the adjacent non-neoplastic breast tissue of 19 breast cancer patients by quantitative reverse transcriptase polymerase chain reaction. In non-neoplastic breast specimens the expression levels of all detected VEGF-A-isoforms (189, 165, 121) were significantly higher in premenopausal compared to post-menopausal women (P = 0.02) and were inversely correlated with the patient's age (P = 0.006). In contrast, in cancerous tissues menopausal status had no influence on VEGF-A-expression levels. Benign and malignant tissues exhibited a similar expression pattern of VEGF-A-isoforms relative to each other. Thus, the regulation of the vasculature in normal breast tissue, as opposed to breast cancer tissue, appears to be hormonally dependent. Endogenous and therapeutically used hormonal steroids might, therefore, cause clinically relevant changes of the angiogenic phenotype of the human breast. © 1999 Cancer Research Campaign

Keywords: breast cancer, angiogenesis, VEGF, steroid hormones, menopause

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Selected References

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  1. Anan K., Morisaki T., Katano M., Ikubo A., Kitsuki H., Uchiyama A., Kuroki S., Tanaka M., Torisu M. Vascular endothelial growth factor and platelet-derived growth factor are potential angiogenic and metastatic factors in human breast cancer. Surgery. 1996 Mar;119(3):333–339. doi: 10.1016/s0039-6060(96)80120-6. [DOI] [PubMed] [Google Scholar]
  2. Benoy I., Vermeulen P., Wuyts H., Dirix L. Vascular endothelial cell growth factor (VEGF) serum concentrations change according to the phase of the menstrual cycle. Eur J Cancer. 1998 Jul;34(8):1298–1299. doi: 10.1016/s0959-8049(98)00066-5. [DOI] [PubMed] [Google Scholar]
  3. Bini L., Magi B., Marzocchi B., Arcuri F., Tripodi S., Cintorino M., Sanchez J. C., Frutiger S., Hughes G., Pallini V. Protein expression profiles in human breast ductal carcinoma and histologically normal tissue. Electrophoresis. 1997 Dec;18(15):2832–2841. doi: 10.1002/elps.1150181519. [DOI] [PubMed] [Google Scholar]
  4. Brown L. F., Berse B., Jackman R. W., Tognazzi K., Guidi A. J., Dvorak H. F., Senger D. R., Connolly J. L., Schnitt S. J. Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in breast cancer. Hum Pathol. 1995 Jan;26(1):86–91. doi: 10.1016/0046-8177(95)90119-1. [DOI] [PubMed] [Google Scholar]
  5. Buadu L. D., Murakami J., Murayama S., Hashiguchi N., Sakai S., Masuda K., Toyoshima S., Kuroki S., Ohno S. Breast lesions: correlation of contrast medium enhancement patterns on MR images with histopathologic findings and tumor angiogenesis. Radiology. 1996 Sep;200(3):639–649. doi: 10.1148/radiology.200.3.8756909. [DOI] [PubMed] [Google Scholar]
  6. Chung H. C., Rha S. Y., Ahn J. B., Shim K. Y., Yoo N. C., Kim J. H., Roh J. K., Lee K. S., Min J. S., Kim B. S. Menstrual state should be considered in determining sero-positivity of soluble angiogenic factors in breast cancer. Int J Mol Med. 1998 Oct;2(4):465–470. doi: 10.3892/ijmm.2.4.465. [DOI] [PubMed] [Google Scholar]
  7. Dickson R. B. Regulation of tumor-host interactions in breast cancer. J Steroid Biochem Mol Biol. 1992 Mar;41(3-8):389–400. doi: 10.1016/0960-0760(92)90364-o. [DOI] [PubMed] [Google Scholar]
  8. Ferrara N., Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev. 1997 Feb;18(1):4–25. doi: 10.1210/edrv.18.1.0287. [DOI] [PubMed] [Google Scholar]
  9. Gasparini G., Toi M., Gion M., Verderio P., Dittadi R., Hanatani M., Matsubara I., Vinante O., Bonoldi E., Boracchi P. Prognostic significance of vascular endothelial growth factor protein in node-negative breast carcinoma. J Natl Cancer Inst. 1997 Jan 15;89(2):139–147. doi: 10.1093/jnci/89.2.139. [DOI] [PubMed] [Google Scholar]
  10. Gimbrone M. A., Jr, Leapman S. B., Cotran R. S., Folkman J. Tumor dormancy in vivo by prevention of neovascularization. J Exp Med. 1972 Aug 1;136(2):261–276. doi: 10.1084/jem.136.2.261. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Graven K. K., McDonald R. J., Farber H. W. Hypoxic regulation of endothelial glyceraldehyde-3-phosphate dehydrogenase. Am J Physiol. 1998 Feb;274(2 Pt 1):C347–C355. doi: 10.1152/ajpcell.1998.274.2.C347. [DOI] [PubMed] [Google Scholar]
  12. Greb R. R., Heikinheimo O., Williams R. F., Hodgen G. D., Goodman A. L. Vascular endothelial growth factor in primate endometrium is regulated by oestrogen-receptor and progesterone-receptor ligands in vivo. Hum Reprod. 1997 Jun;12(6):1280–1292. doi: 10.1093/humrep/12.6.1280. [DOI] [PubMed] [Google Scholar]
  13. Hagen A. A., Hrushesky W. J. Menstrual timing of breast cancer surgery. Am J Surg. 1998 Mar;175(3):245–261. doi: 10.1016/s0002-9610(97)00294-8. [DOI] [PubMed] [Google Scholar]
  14. Hanahan D., Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell. 1996 Aug 9;86(3):353–364. doi: 10.1016/s0092-8674(00)80108-7. [DOI] [PubMed] [Google Scholar]
  15. Heer K., Kumar H., Speirs V., Greenman J., Drew P. J., Fox J. N., Carleton P. J., Monson J. R., Kerin M. J. Vascular endothelial growth factor in premenopausal women--indicator of the best time for breast cancer surgery? Br J Cancer. 1998 Nov;78(9):1203–1207. doi: 10.1038/bjc.1998.655. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hlatky L., Tsionou C., Hahnfeldt P., Coleman C. N. Mammary fibroblasts may influence breast tumor angiogenesis via hypoxia-induced vascular endothelial growth factor up-regulation and protein expression. Cancer Res. 1994 Dec 1;54(23):6083–6086. [PubMed] [Google Scholar]
  17. Hyder S. M., Murthy L., Stancel G. M. Progestin regulation of vascular endothelial growth factor in human breast cancer cells. Cancer Res. 1998 Feb 1;58(3):392–395. [PubMed] [Google Scholar]
  18. Le Bihan S., Marsaud V., Mercier-Bodard C., Baulieu E. E., Mader S., White J. H., Renoir J. M. Calcium/calmodulin kinase inhibitors and immunosuppressant macrolides rapamycin and FK506 inhibit progestin- and glucocorticosteroid receptor-mediated transcription in human breast cancer T47D cells. Mol Endocrinol. 1998 Jul;12(7):986–1001. doi: 10.1210/mend.12.7.0128. [DOI] [PubMed] [Google Scholar]
  19. Mukhopadhyay D., Tsiokas L., Sukhatme V. P. Wild-type p53 and v-Src exert opposing influences on human vascular endothelial growth factor gene expression. Cancer Res. 1995 Dec 15;55(24):6161–6165. [PubMed] [Google Scholar]
  20. Müller-Schimpfle M., Ohmenhaüser K., Stoll P., Dietz K., Claussen C. D. Menstrual cycle and age: influence on parenchymal contrast medium enhancement in MR imaging of the breast. Radiology. 1997 Apr;203(1):145–149. doi: 10.1148/radiology.203.1.9122383. [DOI] [PubMed] [Google Scholar]
  21. Nakamura J., Savinov A., Lu Q., Brodie A. Estrogen regulates vascular endothelial growth/permeability factor expression in 7,12-dimethylbenz(a)anthracene-induced rat mammary tumors. Endocrinology. 1996 Dec;137(12):5589–5596. doi: 10.1210/endo.137.12.8940388. [DOI] [PubMed] [Google Scholar]
  22. Obermair A., Kucera E., Mayerhofer K., Speiser P., Seifert M., Czerwenka K., Kaider A., Leodolter S., Kainz C., Zeillinger R. Vascular endothelial growth factor (VEGF) in human breast cancer: correlation with disease-free survival. Int J Cancer. 1997 Aug 22;74(4):455–458. doi: 10.1002/(sici)1097-0215(19970822)74:4<455::aid-ijc17>3.0.co;2-8. [DOI] [PubMed] [Google Scholar]
  23. Pham C. D., Roberts T. P., van Bruggen N., Melnyk O., Mann J., Ferrara N., Cohen R. L., Brasch R. C. Magnetic resonance imaging detects suppression of tumor vascular permeability after administration of antibody to vascular endothelial growth factor. Cancer Invest. 1998;16(4):225–230. doi: 10.3109/07357909809039771. [DOI] [PubMed] [Google Scholar]
  24. Rak J., Filmus J., Kerbel R. S. Reciprocal paracrine interactions between tumour cells and endothelial cells: the 'angiogenesis progression' hypothesis. Eur J Cancer. 1996 Dec;32A(14):2438–2450. doi: 10.1016/s0959-8049(96)00396-6. [DOI] [PubMed] [Google Scholar]
  25. Scott P. A., Gleadle J. M., Bicknell R., Harris A. L. Role of the hypoxia sensing system, acidity and reproductive hormones in the variability of vascular endothelial growth factor induction in human breast carcinoma cell lines. Int J Cancer. 1998 Mar 2;75(5):706–712. doi: 10.1002/(sici)1097-0215(19980302)75:5<706::aid-ijc8>3.0.co;2-2. [DOI] [PubMed] [Google Scholar]
  26. Scott P. A., Smith K., Poulsom R., De Benedetti A., Bicknell R., Harris A. L. Differential expression of vascular endothelial growth factor mRNA vs protein isoform expression in human breast cancer and relationship to eIF-4E. Br J Cancer. 1998 Jun;77(12):2120–2128. doi: 10.1038/bjc.1998.356. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Toi M., Inada K., Suzuki H., Tominaga T. Tumor angiogenesis in breast cancer: its importance as a prognostic indicator and the association with vascular endothelial growth factor expression. Breast Cancer Res Treat. 1995;36(2):193–204. doi: 10.1007/BF00666040. [DOI] [PubMed] [Google Scholar]
  28. Villena-Heinsen C., Ertan A. K., Holländer M., König J., Tossounidis I., Schmidt W. Diagnostische und prognostische Wertigkeit des Gefässwiderstandes bei Brusttumoren. Ultraschall Med. 1998 Feb;19(1):10–15. doi: 10.1055/s-2007-993980. [DOI] [PubMed] [Google Scholar]
  29. Vogel P. M., Georgiade N. G., Fetter B. F., Vogel F. S., McCarty K. S., Jr The correlation of histologic changes in the human breast with the menstrual cycle. Am J Pathol. 1981 Jul;104(1):23–34. [PMC free article] [PubMed] [Google Scholar]
  30. Wright P. S., Cross-Doersen D. E., Chmielewski P. A., Bush T. L., Bitonti A. J., Miller J. A. Measurement of mRNA levels in tumor xenografts with quantitative autoradiography and in situ hybridization. FASEB J. 1995 Feb;9(2):279–283. doi: 10.1096/fasebj.9.2.7781931. [DOI] [PubMed] [Google Scholar]
  31. Wright P. S., Loudy D. E., Cross-Doersen D. E., Montgomery L. R., Sprinkle-Cavallo J., Miller J. A., Distler C. M., Lower E. E., Woessner R. D. Quantitation of vascular endothelial growth factor mRNA levels in human breast tumors and metastatic lymph nodes. Exp Mol Pathol. 1997 Feb;64(1):41–51. doi: 10.1006/exmp.1997.2208. [DOI] [PubMed] [Google Scholar]
  32. Yoshiji H., Gomez D. E., Shibuya M., Thorgeirsson U. P. Expression of vascular endothelial growth factor, its receptor, and other angiogenic factors in human breast cancer. Cancer Res. 1996 May 1;56(9):2013–2016. [PubMed] [Google Scholar]

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