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Press Release No. 16
/ September 09, 2005 /
Berlin

Molecular Uptake for Sex Hormones

How do sex hormones such as androgens and estrogens reach their final destination in the body? Scientists in Germany and Denmark have unravelled a new mechanism of how sex hormones enter those cells that are in need of them. They have been able to demonstrate that a receptor called megalin (Greek: mega = “big”) on the surface of these cells is able to recognize the transport particle that cargoes steroid hormones in the bloodstream, steering this package loaded with hormones into the cell. Thus, Megalin actually functions as a reception for delivery of sex hormones. Up until now, scientists assumed that steroid hormones simply flood all cells, regardless of whether they are needed or not. “According to our findings, this free hormone hypothesis does not hold true for all cases, at least not for androgens and estrogens. Some tissues which require large amounts of sex steroids have developed a specific mechanism for the active uptake of these important regulators”, explained Prof. Thomas Willnow from the Max Delbrueck Center for Molecular Medicine (MDC) Berlin-Buch. The studies by Dr. Annette Hammes (MDC) in the group of Prof. Willnow and their colleagues at the University of Aarhus (Denmark) has now been published in the scientific journal Cell*(Vol. 122, DOI 10.1016/j.cell.2005.06.032).

Are there Megalin receptors on breast cancer cells?

These new findings have important implications for cancer research. Many breast tumors depend on sex hormones for growth. These tumors are treated with therapeutic drugs such as tamoxifen that block steroid hormone receptors in the nucleus of the cancer cell and stop their growth. However, this therapy also affects healthy cells and prevents them from responding to sex hormones when needed. Now the MDC researchers want to find out if breast cancer cells also carry specific receptors for the uptake of sex hormones not present on normal cells. If so, these receptors may become new important targets for cancer therapy. The MDC researchers began pursuing their research project following results obtained a few years ago. At that time, Prof. Willnow and his group demonstrated that vitamin D (also a steroid hormone) enters kidney cells via the megalin receptor. Megalin is a member of the LDL receptor family of cell surface receptors which regulate the cellular uptake of cholesterol. Steroid hormones are derived from cholesterol and behave in a similar way. They are water insoluble and have to be packaged into transport particles before being carried through the blood. For the male and female sex hormones, androgens and estrogens, respectively, this carrier is the protein sex binding globulin (SHBG), the structure of which was deciphered by Prof. Udo Heinemann from the MDC. In cell culture and in animal experiments, Dr. Hammes and her colleagues were able to demonstrate that megalin recognizes SHBG with its hormone cargo and transports it into steroid-dependent cells. Mice which lack megalin are unable to take up sex hormones. As a consequence of this defect, their reproductive organs are incompletely developed and the animals are infertile.

* Impaired development of the reproductive organs in mice lacking megalin, an endocytic receptor for steroid hormones"

Annette Hammes*+, Thomas K. Andreassen'+, Robert Spoelgen*+, Jens Raila#, Norbert Hubner*, Herbert Schulz*, Jochen Metzger§, Florian J. Schweigert#, Peter B. Luppa§, Anders Nykjaer' and Thomas Willnow*

Max-Delbrueck-Center for Molecular Medicine, Berlin

Institute of Nutritional Science, University of Potsdam, Potsdam-Rehbrücke

Institute for Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar

Technical University, Munich, Germany

'Department of Medical Biochemistry, University of Aarhus and ReceptIcon ApS, Aarhus, Denmark

+ These authors contributed equally to the study.

Barbara Bachtler
Press and Public Affairs
Max-Delbrück-Center for Molecular Medicine (MDC)
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e-mail:presse@mdc-berlin.de
http://www.mdc-berlin.de/en/news

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