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Estradiol increases VEGF in normal human breast studied by whole-tissue culture
Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Burn Unit . Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Plastic Surgery, Hand Surgery and Burns . Linköping University, Faculty of Health Sciences.
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2006 (English)In: Cell Tissue Research, ISSN 0302-766X, Vol. 325, no 2, 245-251 p.Article in journal (Refereed) Published
Abstract [en]

Sex steroid exposure constitutes a risk factor for breast cancer, but little is known about the effects of sex steroids on the normal breast, largely because of the lack of convenient models. We have developed a method of culturing normal breast tissue ex vivo. We have applied this method to investigate the effects of estradiol and progesterone on the key angiogenic mediator, vascular endothelial growth factor (VEGF), in the breast. Whole breast tissue was obtained from routine reduction mammoplasty. Tissue biopsies were cultured in vitro for 1–3 weeks, and the expression of luminal cytokeratin 18 was determined by immunohistochemistry. As an application, tissue biopsies were treated in vitro for 1 week with or without estradiol or estradiol and progesterone. Estrogen receptor, progesterone receptor, and Ki–67 were analyzed, and VEGF levels were examined by quantitative immunoassay and immunohistochemistry. Whole breast tissue was cultured ex vivo for 1 week with preserved morphology. Increased detachment of the luminal epithelium was observed after 2 weeks. Estradiol increased extracellular levels of VEGF in normal breast tissue biopsy medium. The addition of progesterone had neither stimulatory nor inhibitory effects on secreted VEGF. The method of whole breast tissue culturing thus provide a means by which to explore the biology of normal breast tissue. Our results suggest that estradiol exerts pro-angiogenic effects in normal breast by increasing levels of biologically active VEGF.

Place, publisher, year, edition, pages
2006. Vol. 325, no 2, 245-251 p.
Keyword [en]
Angiogenesis, Vascular endothelial growth factor, Cytokeratin 18, Extracellular expression, Luminal expression, Estradiol, Progesterone, Human
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-13941DOI: 10.1007/s00441-006-0159-7OAI: oai:DiVA.org:liu-13941DiVA: diva2:22269
Available from: 2006-08-29 Created: 2006-08-29
In thesis
1. Effects of sex steroids and tamoxifen on VEGF in the breast
Open this publication in new window or tab >>Effects of sex steroids and tamoxifen on VEGF in the breast
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Sex steroid exposure constitutes a risk factor for breast cancer, but little is known about the effects of sex steroids on factors mediating angiogenesis, the development of new blood vessels, in normal and malignant breast tissue. In this thesis we have investigated the effects of estradiol, progesterone, and the nonsteroidal anti-estrogen tamoxifen on vascular endothelial growth factor (VEGF) and its receptors (VEGFR-1 and VEGFR-2) in normal human breast tissue, endothelial cells, and breast cancer. We have applied the technique of microdialysis to provide in situ sampling of estradiol and VEGF in tumors and normal breast tissue of breast cancer patients in vivo. Furthermore, we present a novel method of culturing normal human breast tissue ex vivo.

Our results suggest a pro-angiogenic effect of estradiol and an anti-angiogenic effect of tamoxifen in the breast. Estradiol increased extracellular levels of VEGF in normal human breast tissue and breast cancer cells in vitro. In addition, estradiol decreased sVEGFR-1 in breast cancer cells and indirectly increased VEGFR-2 in endothelial cells. Compared to estradiol treatment alone, estradiol + tamoxifen increased sVEGFR-1 and decreased VEGF in breast cancer cells in vitro. Furthermore, estradiol + tamoxifen decreased tumor VEGF levels and tumor vasculature in human breast cancer xenografts in vivo. In breast cancer patients, a significant correlation was found between in vivo levels of estradiol and VEGF sampled by microdialysis in normal human breast tissue, suggesting that estradiol may be a potent regulator of VEGF in the breast in vivo. Tumor levels of VEGF were significantly higher than in normal breast tissue in vivo, supporting the role of VEGF in tumor angiogenesis. For studies of normal human breast, whole breast tissue may be cultured in vitro for up to one week with preserved morphology. Using this method, estradiol, and not progesterone, appears to be the main sex steroid regulator of extracellular VEGF in normal breast tissue. In conclusion, the data suggest that sex steroids and tamoxifen exert pro- and anti-angiogenic effects in normal breast tissue and breast cancer.

Place, publisher, year, edition, pages
Institutionen för biomedicin och kirurgi, 2006
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 953
Keyword
angiogenesis, breast cancer, estradiol, MCF-7, microdialysis, nude mice, progesterone, sVEGFR-1, VEGFR-2
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-7230 (URN)91-85497-91-6 (ISBN)
Public defence
2006-09-22, Berzeliussalen, Faculty of Health Sciences, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2006-08-29 Created: 2006-08-29 Last updated: 2009-08-22

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Garvin, StinaNilsson, Ulrika W.Huss, Fredrik R. M.Kratz, GunnarDabrosin, Charlotta

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