Cell Res: breast cancer gene prevention can be achieved?

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Source: Oncology InformationAustria Molecular Biology Technology Research Institute (IMBA) and Maryland University School of medicine, the i

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Source: Oncology Information

Austria Molecular Biology Technology Research Institute (IMBA) and Maryland University School of medicine, the international team found that hereditary breast cancer can significantly inhibit the expression of a gene to prevent bone, and an accredited drug can be quickly put into use and can be used as the first breast cancer prevention drug. The discovery was contained in the May 2016 Cell Research.

background

Breast cancer is the most common malignant tumors in women, about 1/8 in the life of women can develop invasive breast cancer, in addition to hormones and environmental factors, such as BRCA1 or BRCA2 gene mutations can also increase the risk of breast cancer. On average, women with this mutation had a 87% chance of developing breast cancer in their lifetime, and some of them were very early. To date, prophylactic surgery is the only surgical procedure that significantly reduces the risk of breast cancer, but it can also cause postoperative complications.

In 2010, researchers from Jose Penninger, IMBA, and his team have found that sex hormones can induce breast cancer through a key factor in bone metabolism, called RANKL, and its receptor. In breast cells, RANKL and RANK are also linked to sex hormones -- a signal that causes the cells to proliferate. The process normally occurs in every woman during pregnancy and menstruation. However, if it is down regulated, the mammary gland cells begin to divide and differentiate into each other and become immortal.

Methods & results

Now, a multinational study has found that RANKL is also a major driver of BRCA1 mutations in breast cancer. From the research group Penninger Verena Sigl found that in mouse mammary epithelial cells and osteoclast differentiation factor RANK gene inactivation of the Brca1 key, and p53 mutation driven breast cancer can reduce the incidence of tumor aggressiveness, and progress to higher grade tumors reduce delay. Long term inhibition of RANK ligand RANKL in mice can inhibit the occurrence of precancerous lesions driven by BRCA1 mutations. On the other hand, the inactivation of RANK gene or the blockade of RANKL/RANK attenuated the proliferation and proliferation of mammary stem cells in Brca1 and p53 mutant mice.

In order to determine their results are correlated with the human, the scientists have isolated due to mutations in the BRCA1 gene and the prophylactic mastectomy of female breast tissue cells. Inhibition of RANKL also resulted in a significant reduction in cell growth and proliferation in human breast cells.

In addition, RANKL and RANK were highly expressed in precancerous lesions and breast cancer tissues of human BRCA mutation carriers. The scientists tested more than 23000 women and found that the RANK gene mutation was associated with a higher risk of breast cancer in women with BRCA1 and BRCA2 mutations. Therefore, RANKL/RANK can restrict the expansion of progenitor cells and tumorigenesis in hereditary breast cancer.

These results provide a series of feasible strategies for preventing breast cancer in patients with BRCA1 mutation. "We found that is so exciting, because there is already an approved anti RANKL drugs" (currently Denosumab Kennedy)". This is a side effect of an antibody that can be closely linked with RANKL, thereby inhibiting its activity. Based on our findings, or other approved drugs currently Di could block future drug RANKL/RANK, for BRCA mutation carriers do breast cancer prevention, "Verena Sigl explains.

Scientists at the University of Maryland School of medicine have tried to prevent the use of RANKL blocking drugs in mice. Animals carrying BRCA1 mutations were divided into two groups: the control group, which produced a variety of early breast cancer lesions; the experimental group showed little change in breast tissue over a longer period of time. Careful phase III trials are now needed to confirm efficacy in humans.

Significance

In the future, any woman who has been tested for BRCA1 mutations can take RANKL inhibitors as a preventive measure, which can greatly reduce the risk of breast cancer. Josef Penninger also said: "this work is a good example of the international cooperation of many scientists in order to prevent breast cancer. Cancer prevention is one of the key problems in medicine today. We also found that RANKL/RANK is closely associated with sex hormone driven breast cancer. If the mechanism found is effective in the prevention of high-risk breast cancer patients, it may be used for routine prevention of breast cancer. The door to breast cancer prevention is now open and will soon be tested."

Compiled from

Cell Res (2016): 1-14. RANKL/RANK Brca1 mutation-driven mammary control tumors.

 

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