Summary
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.
Similar content being viewed by others
Article PDF
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Anan, K, Morisaki, T, Katano, M, Ikubo, A, Kitsuki, H, Uchiyama, A, Kuroki, S, Tanaka, M & Torisu, M (1996). Vascular endothelial growth factor and platelet-derived growth factor are potential angiogenic and metastatic factors in human breast cancer. Surgery 119: 333–339.
Beatson, GT (1896). 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.
Benoy, I, Vermeulen, P, Wuyts, H & Dirix, L (1998). Vascular endothelial cell growth factor (VEGF) serum concentrations change according to the phase of the menstrual cycle. Eur J Cancer 34: 1298–1299.
Bini, L, Magi, B, Marzocchi, B, Arcuri, F, Tripodi, S, Cintorino, M, Sanchez, JC, Frutiger, S, Hughes, G, Pallini, V, Hochstrasser, DF & Tosi, P (1997). Protein expression profiles in human breast ductal carcinoma and histologically normal tissue. Electrophoresis 18: 2832–2841.
Brown, LF, Berse, B, Jackman, RW, Tognazzi, K, Guidi, AJ, Dvorak, HF, Senger, DR, Connolly, JL & Schnitt, SJ (1995). Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in breast cancer. Hum Pathol 26: 86–91.
Buadu, LD, Murakami, J, Murayama, S, Hashiguchi, N, Sakai, S, Masuda, K, Toyoshima, S, Kuroki, S & Ohno, S (1996). Breast lesions: correlation of contrast medium enhancement patterns on MR images with histopathologic findings and tumor angiogenesis. Radiology 200: 639–649.
Chung, HC, Rha, SY, Ahn, JB, Shim, KY, Yoo, NC, Kim, JH, Roh, JK, Lee, KS, Min, JS, Kim, BS & Kim, JJ (1998). Menstrual state should be considered in determining sero-positivity of soluble angiogenic factors in breast cancer. Int J Mol Med 2: 465–470.
Dickson, RB (1992). Regulation of tumor–host interactions in breast cancer. J Steroid Biochem Mol Biol 41: 389–400.
Ferrara, N & Davis-Smyth, T (1997). The biology of vascular endothelial growth factor. Endocr Rev 18: 4–25.
Gasparini, G, Toi, M, Gion, M, Verderio, P, Dittadi, R, Hanatani, M, Matsubara, I, Vinante, O, Bonoldi, E, Boracchi, P, Gatti, C, Suzuki, H & Tominaga, T (1997). Prognostic significance of vascular endothelial growth factor protein in node negative breast carcinoma. J Natl Cancer Inst 89: 139–147.
Gimbrone, MA Jr, Leapman, SB, Cotran, RS & Folkman, J (1972). Tumor dormancy in vivo by prevention of neovascularization. J Exp Med 136: 261–276.
Graven, KK, McDonald, RJ & Farber, HW (1998). Hypoxic regulation of endothelial glyceraldehyde-3-phosphate dehydrogenase. Am J Physiol 274: C347–355.
Greb, RR, Heikinheimo, O, Williams, RF, Hodgen, GD & Goodman, AL (1997). Vascular endothelial growth factor in primate endometrium is regulated by oestrogen receptor and progesterone receptor ligands in vivo. Hum Reprod 12: 1280–1292.
Hagen, AA & Hrushesky, WJM (1998). Menstrual timing of breast cancer surgery. Am J Surg 175: 245–261.
Hanahan, D & Folkman, J (1996). Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86: 353–364.
Heer, K, Kumar, H, Speirs, V, Greenman, J, Drew, PJ, Fox, JN, Carleton, PJ, Monson, JRT & Kerin, MJ (1998). Vascular endothelial growth factor in premenopausal women: indicator of the best time for breast cancer surgery?. Br J Cancer 78: 1203–1207.
Hlatky, L, Tsionou, C, Hahnfeldt, P & Coleman, CN (1994). Mammary fibroblasts may influence breast tumor angiogenesis via hypoxia-induced vascular endothelial growth factor up-regulation and protein expression. Cancer Res 54: 6083–6086.
Hyder, SM, Murthy, L & Stancel, GM (1998). Progestin regulation of vascular endothelial growth factor in human breast cancer cells. Cancer Res 58: 392–395.
Le-Bihan, S, Marsaud, V, Mercier-Bodard, C, Baulieu, EE, Mader, S, White, JH & Renoir, JM (1998). 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 12: 986–1001.
Müller-Schimpfle, M, Ohmenhäuser, K, Stoll, P, Dietz, K & Claussen, CD (1997). Menstrual cycle and age: influence on parenchymal contrast medium enhancement in MR imaging of the breast. Radiology 203: 145–149.
Mukhopadhyay, D, Tsiokas, L & Sukhatme, VP (1995). Wild-type p53 and v-src exert opposing influences on human vascular endothelial growth factor gene expression. Cancer Res 55: 6161–6165.
Nakamura, J, Savinov, A, Lu, Q & Brodie, A (1996). Estrogen regulates vascular endothelial growth permeability factor expression in 7,12-dimethylbenz(a)anthracene-induced rat mammary tumors. Endocrinology 137: 5589–5596.
Obermair, A, Kucera, E, Mayerhofer, K, Speiser, P, Seifert, M, Czerwenka, K, Kaider, A, Leodolter, S, Kainz, C & Zeillinger, R (1997). Vascular endothelial growth factor (VEGF) in human breast cancer: correlation with disease free survival. Int J Cancer 74: 455–458.
Pham, CD, Roberts, TPL, vanBruggen, N, Melnyk, O, Mann, J, Ferrara, N, Cohen, RL & Brasch, RC (1998). Magnetic resonance imaging detects suppression of tumor vascular permeability after administration of antibody to vascular endothelial growth factor. Cancer Invest 16: 225–230.
Rak, J, Filmus, J & Kerbel, RS (1996). Reciprocal paracrine interactions between tumour cells and endothelial cells: the angiogenesis progression hypothesis. Eur J Cancer 32A: 2438–2450.
Scott, PAE, Gleadle, JM, Bicknell, R & Harris, AL (1998a). 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. Intern J Cancer 75: 706–712.
Scott, PAE, Smith, K, Poulsom, R, Debenedetti, A, Bicknell, R & Harris, AL (1998b). Differential expression of vascular endothelial growth factor MRNA vs protein isoform expression in human breast cancer and relationship to eIF-4E. Br J Cancer 77: 2120–2128.
Toi, M, Inada, K, Suzuki, H & Tominaga, T (1995). Tumor angiogenesis in breast cancer: its importance as a prognostic indicator and the association with vascular endothelial growth factor expression. Breast Cancer Res Treat 36: 193–204.
Villena-Heinsen, C, Ertan, AK, Hollander, M, Konig, J, Tossounidis, I & Schmidt, W (1998). Diagnostic and predictive ranking of the vascular resistance index in breast tumours. Ultraschall in der Medizin 19: 10–15.
Vogel, PM, Georgiade, NG, Fetter, BF, Vogel, FS & McCarty, KS Jr (1981). The correlation of histologic changes in the human breast with the menstrual cycle. Am J Pathol 104: 23–34.
Wright, PS, Cross-Doersen, DE, Chmielewski, PA, Bush, TL, Bitonti, AJ & Miller, JA (1995). Measurement of mRNA levels in tumor xenografts with quantitative autoradiography and in situ hybridization. FASEB J 9: 279–283.
Wright, PS, Loudy, DE, Cross-Doersen, DE, Montgomery, LR, Sprinkle-Cavallo, J, Miller, JA, Distler, CM, Lower, EE & Woessner, RD (1997). Quantitation of vascular endothelial growth factor mRNA levels in human breast tumors and metastatic lymph nodes. Exp Mol Pathol 64: 41–51.
Yoshiji, H, Gomez, DE, Shibuya, M & Thorgeirsson, UP (1996). Expression of vascular endothelial growth factor, its receptor, and other angiogenic factors in human breast cancer. Cancer Res 56: 2013–2016.
Author information
Authors and Affiliations
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Greb, R., Maier, I., Wallwiener, D. et al. Vascular endothelial growth factor A (VEGF-A) mRNA expression levels decrease after menopause in normal breast tissue but not in breast cancer lesions. Br J Cancer 81, 225–231 (1999). https://doi.org/10.1038/sj.bjc.6690681
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.bjc.6690681