A new finding provides fresh hope for the millions of women worldwide with estrogen receptor positive breast cancer. Australian scientists have shown that a specific change, which occurs when tumours become resistant to anti-estrogen therapy, might make the cancers susceptible to treatment with chemotherapy drugs.
Seventy percent of breast cancer patients have estrogen receptor positive cancer, and most patients respond well to anti-estrogen therapies, for a few years at least. Within 15 years, however, 50% will relapse and eventually die from the disease.
Dr Andrew Stone, Professor Susan Clark and Professor Liz Musgrove, from Sydney's Garvan Institute of Medical Research, in collaboration with scientists from Cardiff University, have demonstrated that the BCL-2 gene becomes epigenetically 'silenced' in resistant tumours. This process is potentially detectable in the blood, providing a diagnostic marker. Their findings are now online in the international journal Molecular Cancer Therapetics.
Epigenetics involves biochemical changes in our cells that directly impact our DNA, making some genes active, while silencing others. Epigenetic events include DNA methylation, when a methyl group -- one carbon atom and three hydrogen atoms -- attaches to a gene, determining the extent to which it is 'switched on' or 'switched off'.
Dr Stone and colleagues have shown in human disease, as well as in several different cell models, that BCL-2 is silenced in estrogen-resistant tumours by DNA methylation.
"The main purpose of the BCL-2 gene is to keep cells alive, so when the gene is silenced, cells become more vulnerable to chemotherapy," said Dr Stone.
"The next step will be to test our findings in clinical studies. We propose that if the BCL-2 gene is silenced, patients with estrogen receptor positive breast cancer would benefit from combination therapy. In other words, tamoxifen could be used in combination with a chemotherapy drug, to kill off vulnerable tumour cells."
"Excitingly, this is something that could be implemented into clinical practice very quickly, since the technology now exists to profile methylation of BCL-2 in all patients -- both estrogen responsive and estrogen resistant patients. In addition, the proposed chemotherapy drugs are already in use."
"If such a test were to be implemented, we believe it could help patients much earlier -- hopefully shutting down tumours at an early stage."
Estrogen is a hormone produced by all women, and drives reproduction, menstruation and menopause. Many breast cells have estrogen receptors on their surface. When one of those cells becomes malignant and starts to multiply, an estrogen receptor positive tumour develops. Typically these tumours are fed by high concentrations of estrogen in the bloodstream, triggered by circumstances such as late first pregnancy, not breastfeeding, or too much body fat.
At present, there are three different therapeutic strategies for estrogen receptor positive breast cancer: blocking the body's production of estrogen with aromatase inhibitors; preventing estrogen from 'binding' to the estrogen receptor by 'binding' the drug tamoxifen instead; and destroying the estrogen receptor completely.
Tamoxifen, now the gold standard treatment, became available in the 1970s.
Endocrine therapies, including tamoxifen, are inexpensive and well-tolerated, and are usually given for 5 years. Over time, however, many tumours become resistant to therapy. When one form of treatment starts to fail, a second is put in place, and then a third. Response times shrink, and tumours start to spread to other parts of the body, usually the brain, lungs, liver and bone.
At this late stage, there is little that can be done to help someone, as the brain, lungs, liver and bone are parts of the body that cannot be biopsied or operated upon.
- A. Stone, M. J. Cowley, F. Valdes-Mora, R. A. McCloy, C. M. Sergio, D. Gallego-Ortega, C. E. Caldon, C. J. Ormandy, A. V. Biankin, J. M. Gee, R. I. Nicholson, C. G. Print, S. J. Clark, E. A. Musgrove. BCL-2 hypermethylation is a potential biomarker of sensitivity to anti-mitotic chemotherapy in endocrine-resistant breast cancer.. Molecular Cancer Therapeutics, 2013; DOI: 10.1158/1535-7163.MCT-13-0012
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