Advances In Breast And Ovarian Cancer Research

Advances In Breast And Ovarian Cancer Research

It was known that the BRCA-1-BARD-1 protein complex is linked with breast and ovarian cancer.   Subsequent research also found mutations of the BARD-1 BRCA-1 genes in cancer patients. But it was not known if the mutations were cancer pre-disposing or not. A team from Mayo Clinic led by Structural biologist Georges Mer then got down to imaging the whole process of how the BRCA-1-BARD-1 complex repairs broken DNA.

Advances In Breast And Ovarian Cancer Research

In a cell, DNA and histone proteins are formed into complex chromatins, and these chromatins and packed into bundles known as nucleosomes. Damaged DNA is usually repaired by DNA damage response proteins. For this purpose, the DNA damage response proteins need to access the chromatins.  The BRCA-1-BARD-1 protein complex serves to repair broken DNA Strands and this helps in the survival of cells. But this action of the BRCA-1-BARD-1 protein complex could be rendered inactive by cancer cells in order to fight and survive chemotherapy. 

Advances In Breast And Ovarian Cancer Research

This phenomenon needed to be studied in detail and this is where the new technology of cryo-electron microscopy and magnetic resonance spectroscopy came into good use. These techniques helped the researcher team to study the effect of how the BRCA-1-BARD-1 protein complex reacts with the nucleosome and whether this complex is able to modify the chromatin after penetrating the nucleosome. 

The researchers explained how Cyro electron microscopy and magnetic resonance spectroscopy made the functioning of the  BRCA-1-BARD-1 clear and even showed how it identified and interacted with Ubiquitins. 

Bands of BRCA-1-BARD-1 together with nucleosomes are known as macromolecules. The macromolecules are frozen and their image is examined in a Cyro electron microscope. Electron microscopy helps make a 3-D image of the various orientations of the macromolecules. The researchers were then able to use magnetic Resonance Spectroscopy to generate a magnetic field to examine the relative position of atoms within a macromolecule. All these atomic-level imaging techniques helped researchers to observe how BRCA-1-BARD-1 recognizes and interacts with ubiquitin. Ubiquitins signal broken DNA and some can even be found attached to nucleosomes.    

This research was funded by the National Institute of Health, the Mayo Clinic Cancer Center, and the ovarian Research Alliance. Dr. Mer was happy with the results of the research that provided 3D structures that would help doctors recognize variants that were unknown up to now. This recognition would help develop drugs that would neutralize cancer cells more specifically and accurately. Besides effective drug development, this research would facilitate cancer prevention efforts as well 

Mutations in BRCA-1 and BRCA-2 genes have been found to increase the chances of breast and ovarian cancer in women. Other research has also established that hereditary breast cancer due to Mutations in BRCA-1 and BRCA-2 genes was found in 10% to 20% of women affected by cancer in the United States. Ovarian cancer is the second most common gynecological cancer in the United States. These women have had a relative affected with the same type of cancer. These mutations of the BRCA-1 and BRCA-2 genes have a 60 to 85% chance of causing breast cancer and a 15 to 40% chance of developing into ovarian cancer.  

There is strong evidence that there are other high penetrating genes other than BRCA-1 and BRCA-2 genes that increase susceptibility to breast cancer but only BRCA-1 and BRCA-2 are susceptible to ovarian cancer and there are very few others.

There is a recommendation that women undergo prophylactic oophorectomy after they have complete having children since there is presently non another method to detect early forms of these cancers. This procedure will reduce the risk of breast cancer by 60 % and ovarian cancer by 95%. 

 With the detailed 3D structures developed and the additional insight from the research of the team of Dr. Mer, medication and treatment may make prophylactic oophorectomy redundant.  


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