Around 10% of women worldwide will develop breast cancer over the course of their lifetime. Citing data from large population studies, experts now believe that progestins (i.e. synthetic sex hormones) used in hormone replacement therapy (HRT) and contraceptives can raise the risk of breast cancer. Researchers worldwide continue to fight this both common and deadly disease, including a group of EU-funded scientists led by the Vienna-based Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA). The group has identified a key mechanism that permits progestins to affect mammary cells directly. Presented in the journal Nature, the team's research built on previous work by IMBA's Professor Josef Penninger, who discovered the first genetic evidence that the RANKL protein effectively regulates healthy bones by activating the cells that break down bone material when it needs to be replaced. A jumbled system and overproduction of the protein results in bone loss, triggering the brittle bone disorder osteoporosis. Discovering the same molecule in breast tissues helped the researchers connect the dots between breast cancer and sex hormones. Tests on mice confirmed that a synthetic female sex hormone used in HRT and contraceptive pills can activate RANKL in the breast cells of mice. Division and proliferation of the mammary cells start but fail to die when they should, according to the researchers. They add that stem cells in the breast regenerate successfully, leading to breast cancer. Researchers from the US group Amgen meanwhile performed another set of mouse treatment tests and found that pharmacologic blocking of the RANKL system plays a crucial role in delaying mammary tumour formation, which in turn results in fewer breast cancers in mice. Another mouse model showed that RANKL inhibition decreases both breast tumour formation and lung metastasis. 'Ten years ago we formulated the hypothesis that RANKL might be involved in breast cancer and it took us a long time to develop systems to prove this idea,' explains Professor Pennginer, co-author of the study. 'I have to admit it completely surprised me just how massive the effects of the system were. Millions of women take progesterone derivatives in contraceptives and for hormonal replacement therapy. Since our results show that the RANKL system is an important molecular link between a synthetic sex hormone and breast tumours, one day women may be able to reduce their risk by taking blocking medicines in advance to prevent breast cancer.' EU and US officials have approved a monoclonal antibody, called denosumab, to treat osteoporosis. It is now being reviewed for the treatment of bone metastases in patients with advanced cancer. 'Further studies will be needed to prove the principle of our findings,' said lead author Dr Daniel Schramek from IMBA. 'But we hope that medical trials using denosumab can be started in the near future to test whether the mouse studies can be directly translated to human breast cancer.' Researchers from Australia, Canada, Germany, the UK and the US also participated in the study, which was funded in part by the EU projects MASTERSWITCH and INFLA-CARE, as well as a Marie Curie Excellence Grant, worth EUR 1.86 million, and a European Research Council Advanced Grant totalling almost EUR 2.5 million. MASTERSWITCH ('Mechanisms to attack steering effectors of rheumatoid syndromes with innovated therapy choices') received over EUR 11 million and INFLA-CARE ('Understanding inflammation-associated tumorigenesis for the rational design of novel anti-cancer therapeutic strategies') clinched EUR 12 million under the Health Theme of the EU's Seventh Framework Programme (FP7).
Austria, Australia, Canada, Germany, United Kingdom, United States