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How hormones can trigger breast cancer

(Vienna, 29 September 2010) Scientists at the Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences and MedUni Vienna have identified the connection between the intake of synthetic sexual hormones and increased breast cancer risk. Their findings, which have been published electronically in advance by the magazine Nature, foster the hope for preventive measures against hormone-dependent breast cancer. In this context, a new medication against osteoporosis could be applied.

Breast cancer is among the most frequent cancer diseases in western societies. In Europe one in eight women is affected by breast cancer during her lifetime. Only a small portion of patients has inherited the disposition, in most cases the tumour is acquired via external influences. Among the factors facilitating the development of breast cancer is the intake of synthetic progesterones (gestagens) in the course of a hormone replacement therapy or hormonal contraception. Comprehensive long-term trials such as the Million Women Study (UK) and the Women’s Health Initiative (USA) have clearly shown the connection.

A bone gene is the missing link
An international team headed by the Director of IMBA Josef Penninger has now been able to identify the mechanism of how a synthetic sexual hormone can trigger breast cancer in mice. Researchers have for the first time furnished the genetic proof that an important bone gene plays a decisive role here. The majority of trials have been conducted by Daniel Schramek within the framework of his dissertation at IMBA, Lukas Kenner and his team from MedUni Vienna have played a substantial role in the evaluation of the tumours. It has been found at the laboratory of the Department of Clinical Pathology and Ludwig Boltzmann Cancer Research Institute (LBI-CR) at MedUni Vienna that in mice that lack the bone gene RANKL no or a much lower breast cancer growth was observed than in mice where the RANKL gene was active. In addition, the working group headed by Lukas Kenner identified the cell types in the mammary gland from which the malignant growth of the tumours started. With specific antibodies the working group could prove that in rare cases of cancer in which the RANKL gene was not active, most often other subtypes of the mammary gland developed.

The research results, which have now been published, build on earlier work carried out by Josef Penninger who proved the importance of the RANKL protein as a key molecule of the bone metabolism. RANKL is important in the development and degradation of bone substances in that it activates bone-destroying cells. Where RANKL is overactive, the balance tips and osteoporosis develops. Millions of people are affected – they suffer from osteoporosis or a deformity due to bone degradation in the case of rheumatoid arthritis.

Sexual hormones facilitate breast cancer
As early as in 2000 Penninger's employees found that pregnant mice require RANKL to develop functioning milk glands. They were also able to demonstrate that the production of RANKL is triggered by sexual hormones. Based on this data, the researchers assumed that there might be a connection between RANKL and the development of breast cancer. But with the previously used methods it was not possible to prove it.

The group of researchers around Josef Penninger have spent the past ten years developing the right experimental systems to prove their hypothesis. Based on the findings of their studies, it is now possible to deduce the following mechanisms: the synthetic sexual hormone MPA (medroxyprogesterone acetate), which is used in hormone preparations, fosters the production of RANKL in mammary gland cells of mice. This stimulates cell division and, at the same time, protects cells against being eliminated by the body in case of genetic damage. A further consequence is the increase of the stem cell population – all of which are major prerequisites for the development of cancer.

Another work which was published by Nature at the same time supports this model. In this publication, American and Spanish scientists describe experiments on mice in which they triggered breast cancer by administering hormones. Where RANKL was pharmacologically blocked in these mice, the breast cancer rate fell by 90 percent.

Preventing the risk of cancer
Josef Penninger is overwhelmed by the clear study findings. "I am truly surprised how massive the impact of the RANKL system is on the development of breast cancer. Considering that millions of women take synthetic progesterones, this connection is becoming immensely significant. As we now know the mechanisms of tumour development, preventive measures are also conceivable. By taking medication that blocks RANKL, women could possibly reduce their risk of developing breast cancer in the future."

Only a few months ago, a monoclonal antibody was marketed in the US and Europe which blocks RANKL. The substance is approved for use under the name denosumab for the treatment of osteoporosis and bone loss in prostate cancer patients.

"We still have to carry out tests to confirm the validity of our results in humans", says Daniel Schramek. "But we hope very much that trials with denosumab can be launched in the near future."

Testing in connection with this work was conducted at IMBA in cooperation with scientists of the Medical University of Vienna, the Garvan Institute of Medical Research in Sydney, the Ontario Cancer Institute of the University of Toronto, the Harvard School of Public Health, the Harvard Medical School and the Ragon Institute of MGH/MIT and Harvard, the University of Cologne, University College London and the University of Erlangen-Nuremberg.

Original work:
Osteoclast differentiation factor RANKL controls development of progestin-driven mammary cancer (Schramek et al.). Nature AOP, 29.9.2010, doi:10.1038/nature09387
Siehe auch Nature AOP, 29.9.2010, doi:10.1038/nature09495.