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Effects of sex steroids and tamoxifen on matrix metalloproteinase activity and generation of endostatin in the breast
Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
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.

Place, publisher, year, edition, pages
Institutionen för biomedicin och kirurgi , 2007. , 87 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1003
Keyword [en]
Angiogenesis, Breast cancer, TGF-β1, Endostatin, Estradiol, Mammary gland, Matrix metalloproteinases, MCF-7, Microdialysis, Nude mice, Tamoxifen
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:liu:diva-9015ISBN: 978-91-85831-80-7 (print)OAI: oai:DiVA.org:liu-9015DiVA: diva2:23710
Public defence
2007-06-05, Berzeliussalen, Campus US, Linköpings Universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2007-05-30 Created: 2007-05-30 Last updated: 2009-08-22
List of papers
1. MMP‐2 and MMP‐9 activity is regulated by estradiol and tamoxifen in cultured human breast cancer cells
Open this publication in new window or tab >>MMP‐2 and MMP‐9 activity is regulated by estradiol and tamoxifen in cultured human breast cancer cells
2007 (English)In: Breast Cancer Research and Treatment, ISSN 0167-6806, Vol. 102, no 3, 253-261 p.Article in journal (Refereed) Published
Abstract [en]

Sex steroids play a dominant role in breast carcinogenesis by still largely unknown mechanisms. Matrix metalloproteinases (MMPs) have been extensively studied in the context of matrix biology but it is not known if sex steroids affect MMPs in breast cancer. MMPs degrade extracellular matrix components enabling tumor cell invasion and metastasis, but may also regulate the bioavailability of a variety of biologically active molecules such as anti-angiogenic fragments, which may be beneficial for the host. This study shows that estradiol and tamoxifen regulate MMP-2 and MMP-9 as well as TIMP-1 and TIMP-2 in ER + PR + human breast cancer cells. The main finding was a significant effect of tamoxifen exposure, which increased intracellular and secreted protein levels whereas estradiol induced a significant decrease. The overall net effect of these alterations resulted in increased MMP-2/MMP-9 activity by tamoxifen treatment, which also significantly increased extracellular endostatin levels. We conclude that estradiol and tamoxifen have the ability to modulate MMP-2/MMP-9 activity, and endostatin levels in human breast cancer in vitro. The results suggest a possible role of MMP modulation associated with a generation of anti-angiogenic fragments in the therapeutic effect of tamoxifen in breast cancer.

Keyword
Breast cancer, Endostatin, Estrogen, Matrix metalloproteinases, Tamoxifen, Tissue inhibitors of matrix metalloproteinases, MCF-7 cells
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-14550 (URN)10.1007/s10549-006-9335-4 (DOI)
Available from: 2007-05-30 Created: 2007-05-30 Last updated: 2009-08-20
2. Estradiol and tamoxifen regulate endostatin generation via matrix metalloproteinase activity in breast cancer in vivo
Open this publication in new window or tab >>Estradiol and tamoxifen regulate endostatin generation via matrix metalloproteinase activity in breast cancer in vivo
2006 (English)In: Cancer Research, ISSN 0008-5472, Vol. 66, no 9, 4789-4794 p.Article in journal (Refereed) Published
Abstract [en]

Matrix metalloproteinases (MMP) are important regulators of tumor progression and angiogenesis. MMPs generate both proangiogenic and antiangiogenic fragments, such as vascular endothelial growth factor and endostatin. The in vivo activation of MMPs and endostatin generation occur mainly in the extracellular environment by interactions of different cell types. Therefore, these processes are necessary to study in the extracellular space in vivo. Sex steroids play a dominant role in breast carcinogenesis, by largely unknown mechanisms. In the present study, we used in vivo microdialysis to directly quantify MMP-2 and MMP-9 activity and sample endostatin from both stroma (murine) and tumor (human) cells in vivo in solid MCF-7 tumors in nude mice. We found that tamoxifen in combination with estradiol increased tumor MMP-2/MMP-9 in vivo activity, endostatin levels, and decreased tumor vascularization compared with estradiol treatment only. The stroma-derived endostatin was three to five times higher than cancer cell–generated endostatin. After inhibition of MMP-2/MMP-9, endostatin levels decreased, providing evidence that these proteases are highly involved in the generation of endostatin. Our results support the previously reported concept that MMPs may serve as negative regulators of angiogenesis. The regulation of endostatin generation by modulation of MMP-2/MMP-9 activities suggests a previously unrecognized mechanism of estradiol and tamoxifen, which may have implications for the pathogenesis of breast cancer.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-14551 (URN)10.1158/0008-5472.CAN-05-4012 (DOI)
Available from: 2007-05-30 Created: 2007-05-30 Last updated: 2009-05-28
3. Tamoxifen downregulatesTGF‐β1 protein levels via matrix metalloproteinase activity in breast cancer in vivo
Open this publication in new window or tab >>Tamoxifen downregulatesTGF‐β1 protein levels via matrix metalloproteinase activity in breast cancer in vivo
2007 (English)Article in journal (Refereed) Submitted
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-14552 (URN)
Available from: 2007-05-30 Created: 2007-05-30
4. Estradiol decreases endostatin levels in normal human breast tissue in vivo
Open this publication in new window or tab >>Estradiol decreases endostatin levels in normal human breast tissue in vivo
Manuscript (Other academic)
Identifiers
urn:nbn:se:liu:diva-14553 (URN)
Available from: 2007-05-30 Created: 2007-05-30 Last updated: 2010-01-13

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Nilsson, Ulrika W.

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