How HRT and the Pill Can Lead to Breast Cancer: New Research Suggests Possible Treatment ScienceDaily (Sep. 29, 2010) Breast cancer is one of the most common cancers, affecting up to one in eight women during their lives in Europe, the UK and USA. Large population studies such as the Women's Health Initiative and the Million Women Study have shown that synthetic sex hormones called progestins used in hormone replacement therapy, HRT, and in contraceptives can increase the risk of breast cancers. Now medical researchers at the Institute of Molecular Biotechnology of the Austrian Academy of Sciences in Vienna have identified a key mechanism which allows these synthetic sex hormones to directly affect mammary cells. The research builds on previous work by Prof Josef Penninger, the IMBA director, who found the first genetic evidence that a protein called RANKL is the master regulator of healthy bones. In a complex system that regulates bone mass, RANKL activates the cells that break down bone material when it needs to be replaced. When the system goes wrong and we make too much of the protein it triggers bone loss, leading to osteoporosis in millions of patients around the world every year. Finding exactly the same molecule in breast tissues led the scientists to the new link between sex hormones and breast cancer. Scientists have uncovered how hormone replacement therapy can increase the risk of breast cancer, according to new research published on Nature s website today (Wednesday 29 September, 2010). They found that the link is a protein molecule RANKL, which is essential to regulate bone mass and which is also involved in milk production. The Austrian researchers have shown that a synthetic progesterone, frequently used in HRT and hormonal contraception, can switch on the activity of RANKL within breast cells, causing them to divide and multiply and preventing them from dying when they should. Moreover, stem cells in the breast become able to renew themselves, ultimately resulting in breast cancer. (Credit: Copyright IMBA)
In a scientific article published in the journal Nature, the research team show that a synthetic female sex hormone used in HRT and contraceptive pills can trigger RANKL in breast cells of mice. As a consequence, these mammary cells start to divide and multiply and fail to die when they should. Moreover, stem cells in the breast become able to renew themselves, ultimately resulting in breast cancer. In a different set of mouse treatment tests, reported in a second Nature article, researchers at Amgen have found that pharmacologic blocking of the RANKL system significantly delays mammary tumor formation leading to significantly fewer breast cancers in mice. In another mouse model, RANKL inhibition not only decreased breast tumor formation but also reduced 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," says Prof Josef Penninger. " 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 tumors, one day women may be able to reduce their risk by taking blocking medicines in advance to prevent breast cancer." A monoclonal antibody, denosumab, that blocks RANKL has been recently approved in the US and the EU for the treatment of osteoporosis, and is currently under review for the treatment of bone metastases in patients with advanced cancer. "Further studies will be needed to prove the principle of our findings," says Dr Daniel Schramek, who carried out the studies with Prof Josef Penninger at the Institute of Molecular Biotechnology in Vienna. "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." This work was an international collaboration between lead researchers at IMBA and scientists at the Medical University of Vienna; the Garvan Institute of Medical Research, Sydney, Australia; the Ontario Cancer Institute, University of Toronto, Toronto, Canada; Harvard School of Public Health, Harvard Medical School and the Ragon Institute of MGH/MIT and Harvard, Boston, USA; the Institute for Genetics, Centre for Molecular Medicine (CMMC), and Cologne Excellence Cluster (CECAD), University of Cologne, Germany; University College London, UK; and the University of Erlangen-Nuremberg, Germany.
Hormone Replacement Therapy Increases Breast Cancer Recurrence, New Study Finds ScienceDaily (Mar. 26, 2008) Hormone replacement therapy (HRT) for peri- and postmenopausal symptoms increases disease recurrence in breast cancer survivors, according to a new article. Previous studies have shown that HRT increases breast cancer incidence in healthy women, but its impact on breast cancer survivors has remained obscure. Observational studies and one small randomized trial had suggested that HRT had no effect or even might reduce recurrence. However, two-year follow-up data from the randomized HABITS (Hormonal Replacement After Breast Cancer --Is It Safe?) trial indicated that survivors who took HRT were more likely to suffer disease recurrence than those who did not take HRT. In the current analysis, Lars Holmberg, M.D., Ph.D., currently at King's College London and his mostly Scandinavian colleagues examined the breast cancer rates for women in the HABITS trial after a median follow-up of four years. At the time of this analysis, 39 (17.6 percent) of the 221 women in the HRT treatment arm had developed breast cancer recurrence or a new breast cancer malignancy, compared with 17 (7.7 percent) of 221 women in the control arm. The estimated 5-year cumulative rate for disease recurrence was 22.2 percent for the HRT arm and 9.5 percent in the control arm, for an absolute increase in risk of 14.2 percent. "The results of the HABITS trial indicate a substantial risk for a new breast cancer event among breast cancer survivors using [HRT]. The risk elevation is in line with the evidence from observational studies and randomized trials that [HRT] increases the risk of breast cancer in healthy women," the authors write. In an accompanying editorial in the Journal of the National Cancer Institute, Kathy I. Pritchard, M.D., of the Sunnybrook Odette Cancer Center in Toronto discusses the results of the HABITS trial and the Women's Health Initiative trial (which showed increased breast cancer risk among healthy women) in the context of the much less worrisome findings from observational studies. Observational studies, she writes, can be misleading because they have inherent biases, such as the types of patients selected for participation in the study. Although a randomized study from Stockholm found no increased risk of breast cancer recurrence among breast cancer survivors taking HRT, there may be key differences between this trial and the HABITS study, including the dosing schedule, the duration of treatment, and the type of hormones used--synthetic versus natural compounds. Those differences leave open several questions.
Despite these issues, the data are clear. "Although randomized data concerning use of HRT for symptomatic intervention in breast cancer survivors are still sparse, it seems that the harmful side effects of HRT have finally been clearly demonstrated," Pritchard writes. Journal reference: Holmberg L, Iversen O-E, Rudenstam CM, Hammar M, Kumpulainen E, et al. Increased Risk of Recurrence After Hormone Replacement Therapy in Breast Cancer Survivors. J Natl Cancer Inst 2008; 100:475-482 Long-Term Hormone Replacement Therapy Increases Breast Cancer Risk Until 5 Years After Use, Study Finds ScienceDaily (May 30, 2008) If hormone replacement therapy is taken over a period of more than five years, the risk of breast cancer will increase. While this risk is considerably elevated during use of hormone medication, it drops back to the original level within about five years after a woman has stopped taking hormones. These new findings from Germany fit with earlier findings in the U.S. "Are you taking or did you take hormones? If yes, which hormone medication and for how long? When did you stop taking hormone replacement medication?" 3,464 breast cancer patients and 6,657 healthy women between the ages of 50 and 74 years participated in a large survey and elicited detailed information about hormone replacement medications they are taking or used to take for relief of menopausal symptoms. The survey was prompted by the "MARIE" case-control study carried out by the German Cancer Research Center (DKFZ) and the University Hospitals in Hamburg-Eppendorf, Germany. The goal of this 6-year study, which was financed by the German Cancer Aid (Deutsche Krebshilfe), was to determine the effect of hormones -- both on their own and in association with other factors -- on breast cancer risk. Women who have taken menopausal hormone therapy before have a 37 percent higher risk of breast cancer than women who have never taken hormone replacement therapy (HRT). During the actual time of HRT use the risk is even elevated by 73 percent. Within five years after cessation of therapy the risk of breast cancer in former HRT users falls back to the level of women who never used HRT. "These results of the MARIE study confirm findings of two U.S. and U.K. studies (Women's Health Initiative Study and Million Women Study) that caused a stir in 2002 and 2003," says Professor Dr. Wilhelm Braendle of Hamburg-Eppendorf University Hospitals, who headed the study. "It has often been argued that the results of the U.S. study could not be applied to Germany where prescription practices are completely different. Therefore, we captured
the various hormone preparations, especially the various progestins, very precisely. We have obtained similar results as the U.S. researchers," Professor Dr. Jenny Chang-Claude of DKFZ summarizes. "With our new data, we provide physicians in Germany with solid information that will help them to advise their patients about the benefits and risks of hormone replacement therapy." The MARIE study also confirms that different hormone preparations have different effects: Compared to the risk of women who have never used HRT, a combined therapy of estrogen and progestin doubles the risk of breast cancer, while use of estrogen alone (estrogen replacement therapy) raises the risk by only 15 percent. However, in both cases the risk increases only if hormones are taken for more than five years. "Hormone replacement therapy also appears to have a different influence on different types of breast cancer," Braendle explains. "The risk of developing one of the less common lobular or tubular breast cancers increases twice as much under HRT as the risk of the common type of ductal carcinoma, which constitutes 40 to 75 percent of all malignant tumors of the breast." Marijuana Compound Shows Promise In Fighting Breast Cancer ScienceDaily (Nov. 26, 2007) A compound found in cannabis may prove to be effective at helping stop the spread of breast cancer cells throughout the body. The study, by scientists at the California Pacific Medical Center Research Institute, is raising hope that CBD, a compound found in Cannabis sativa, could be the first non-toxic agent to show promise in treating metastatic forms of breast cancer. Right now we have a limited range of options in treating aggressive forms of cancer, says Sean D. McAllister, Ph.D., a cancer researcher at CPMCRI and the lead author of the study. Those treatments, such as chemotherapy, can be effective but they can also be extremely toxic and difficult for patients. This compound offers the hope of a non-toxic therapy that could achieve the same results without any of the painful side effects. CBD, a compound found in Cannabis sativa, could be the first non-toxic agent to show promise in treating metastatic forms of breast cancer. (Credit: istockphoto)
The researchers used CBD to inhibit the activity of a gene called Id-1, which is believed to be responsible for the aggressive spread of cancer cells throughout the body, away from the original tumor site. We know that Id-1 is a key regulator of the spread of breast cancer, says Pierre-Yves Desprez, Ph.D., a cancer researcher at CPMCRI and the senior author of the study. We also know that Id-1 has also been found at higher levels in other forms of cancer. So what is exciting about this study is that if CBD can inhibit Id-1 in breast cancer cells, then it may also prove effective at stopping the spread of cancer cells in other forms of the disease, such as colon and brain or prostate cancer. However, the researchers point out that while their findings are promising they are not a recommendation for people with breast cancer to smoke marijuana. They say it is highly unlikely that effective concentrations of CBD could be reached by smoking cannabis. And while CBD is not psychoactive it is still considered a Schedule 1 drug. This study was recently published in the journal Molecular Cancer Therapeutics. The study was primarily funded by the California Breast Cancer Research Program.