Breast cancer is the most common type of cancer among women, with highest death cases, and when the disease is metastatic, it is incurable. The most common type of breast cancer expresses the estrogen receptor. Hormone therapy is very effective in women with this type of metastatic breast cancer, but over time the tumor stops responding to this therapy and it develops resistance to it. Since in most cases the alternative is chemotherapy, a treatment with limited effectiveness and severe side effects, a more effective and tolerable treatment is required.
In order to find such a treatment, a team of researchers from the Oncology Institute led by Prof. Ido Wolf, Dr. Tami Rubinek the director of the Oncology Laboratory, Dr. Keren Merenbakh-Lamin, a senior researcher and Lotem Zinger, a PhD student, was the first to discover several years ago that the main mechanism for hormone therapy resistance are acquired mutations in the estrogen receptor. The mutations occur in about 40% of patients and cause the receptor to function uncontrollably resulting in failure of the hormonal therapy to eradicate the cancerous cells. Clinical studies conducted in leading centers around the world have indicated that the emergence of mutations is associated with the development of a more violent disease and a less favorable prognosis.
In a new study, published in the prestigious journal Clinical Cancer Research and conducted by the researchers at Ichilov, the group examined what causes cancer cells carrying mutations in the estrogen receptor to become more violent. The researchers discovered that cells carrying the mutations have a unique “gene signature” associated with a more aggressive behavior and altered cellular metabolism. These changes cause cells to divide more rapidly and spread to other areas of the body, namely to develop metastases. Experiments in mice have shown that cells carrying the mutations not only form larger tumors but also send metastases to the lungs and liver.
Thus, the researchers discovered a unique mechanism: the cells developed an ability to better utilize nutrients in their environment enabling production of large amounts of building blocks to create new cells. This helps them survive even in extreme deficient situations.
The findings of the new study reveal that tumors harboring estrogen receptor mutations constitute a new subgroup of breast cancer, with unique metabolic requirements. These requirements are potential vulnerabilities and researchers are now working on developing innovative treatment strategies that will inhibit the unique metabolic activity and thus make it susceptible to novel therapies.
from right to left:
Prof. Ido Wolf, Dr. Tami Rubinek, Dr. Keren Merenbakh-Lamin, Lotem Zinger.