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Tamoxifen downregulatesTGF‐β1 protein levels via matrix metalloproteinase activity in breast cancer in vivo
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
2007 (engelsk)Artikkel i tidsskrift (Fagfellevurdert) Submitted
sted, utgiver, år, opplag, sider
2007.
HSV kategori
Identifikatorer
URN: urn:nbn:se:liu:diva-14552OAI: oai:DiVA.org:liu-14552DiVA, id: diva2:23708
Tilgjengelig fra: 2007-05-30 Laget: 2007-05-30
Inngår i avhandling
1. Effects of sex steroids and tamoxifen on matrix metalloproteinase activity and generation of endostatin in the breast
Åpne denne publikasjonen i ny fane eller vindu >>Effects of sex steroids and tamoxifen on matrix metalloproteinase activity and generation of endostatin in the breast
2007 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

Sex steroids are inevitable in women. However, long-term exposure to sex steroids increases the risk of breast cancer. A complete understanding of sex steroid control of the breast and how it relates to breast cancer risk is still lacking. Angiogenesis and proteolytic enzyme activity are crucial for the process by which tumors evolve into a vascularized, invasive phenotype. Matrix metalloproteinases are potent matrixdegrading enzymes that affect several steps in tumor progression including angiogenesis. In the female reproductive organs, sex steroids regulate angiogenesis and MMP activity, yet little is known how sex steroids affect these crucial events in normal and malignant breast tissue.

This thesis elucidates a link between sex steroids, MMP activity, and angiogenesis. It is shown that estradiol down-regulates while tamoxifen up-regulates the protein expression and activity of MMP-2 and MMP-9 in human breast cancer cells in vitro and in human breast cancer xenografts in vivo. The results further suggest that a biological consequence of this regulation may be modulation of tumor angiogenesis. The net effect of adding tamoxifen to estradiol treatment was an increase in extracellular levels of the endogenous angiogenesis inhibitor endostatin and decreased levels of the tumor promoter TGF-β1 compared to estradiol treatment only. This was accompanied by reduced vasculature and decreased tumor growth. Similarly, a regulatory effect of estradiol and tamoxifen on endostatin generation was observed in normal human breast tissue by whole-tissue culture and microdialysis in human breast tissue in situ.

In conclusion, the results presented in this thesis suggest previously unknown mechanisms of action of estradiol and tamoxifen in breast cancer and in normal human breast tissue, and novel means by which estradiol may tip the scale to favor angiogenesis. This knowledge may be important for the understanding of sex steroid dependent breast carcinogenesis and in the future development of tissue-specific preventive as well as therapeutic strategies against breast cancer.

sted, utgiver, år, opplag, sider
Institutionen för biomedicin och kirurgi, 2007. s. 87
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1003
Emneord
Angiogenesis, Breast cancer, TGF-β1, Endostatin, Estradiol, Mammary gland, Matrix metalloproteinases, MCF-7, Microdialysis, Nude mice, Tamoxifen
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-9015 (URN)978-91-85831-80-7 (ISBN)
Disputas
2007-06-05, Berzeliussalen, Campus US, Linköpings Universitet, Linköping, 09:00 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2007-05-30 Laget: 2007-05-30 Sist oppdatert: 2009-08-22

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