Thursday, March 4, 2021

Clusters of P53 Protein Mutations Offer New Treatment Potentials for TNBC

The p53 protein in its natural state, sometimes called “the guardian of the genome,” is a front-line protector against cancer. But the mutant form appears in 50 percent or more of human cancers and in 80 percent of triple-negative breast cancers. It actively blocks cancer suppressors. Researchers at the University of Houston Rice University have discovered the same mutant protein can aggregate into clusters. These in turn nucleate the formation of amyloid fibrils, a prime suspect in cancers as well as neurological diseases like Alzheimer’s. The research was led by Peter Vekilov at the University of Houston (UH) and Anatoly Kolomeisky at Rice University. 

The condensation of p53 into clusters is driven by the destabilization of the protein’s DNA-binding pocket when a single arginine amino acid is replaced with glutamine, they reported. “It’s known that a mutation in this protein is a main source of cancer, but the mechanism is still unknown,” said Kolomeisky, a professor and chair of Rice’s Department of Chemistry and a professor of chemical and biomolecular engineering. “This knowledge gap has significantly constrained attempts to control aggregation and suggest novel cancer treatments,” said Vekilov, the John and Rebecca Moores Professor of Chemical and Biomolecular Engineering and Chemistry at UH. 

The mutant p53 clusters, which resemble those discovered by Vekilov in solutions of other proteins 15 years ago, and the amyloid fibrils they nucleate prompt the aggregation of proteins the body uses to suppress cancer. “This is similar to what happens in the brain in neurological disorders, though those are very different diseases,” Kolomeisky said. 

The p53 mechanism may be similar to those that form functional and pathological solids like tubules, filaments, sickle cell polymers, amyloids and crystals, Vekilov said. Researchers at UH combined 3D confocal images of breast cancer cells taken in the lab of chemical and biomolecular engineer Navin Varadarajan with light scattering and optical microscopy of solutions of the purified protein carried out in the Vekilov lab. Transmission electron microscopy micrographs of cluster and fibril formation contributed by Michael Sherman at the University of Texas Medical Branch at Galveston (UTMB) supported the main result of the study, as did molecular simulations by Kolomeisky’s group All confirmed the p53 mutant known as R248Q goes through a two-step process to form mesoscopic condensates. Understanding the mechanism could provide insight into treating various cancers that manipulate either p53 or its associated signaling pathways, Vekilov said. 

In normal cell conditions, the concentration of p53 is relatively low, so the probability of aggregation is low, he said. But when a mutated p53 is present, the probability increases. “Experiments show the size of these clusters is independent of the concentration of p53,” Kolomeisky said. “Mutated p53 will even take normal p53 into the aggregates. That’s one of the reasons for the phenomenon known as loss of function.” If even a small relative fraction of the mutant is present, it’s enough to kill or lower the ability of normal, wild-type p53 to fight cancer, according to the researchers. 

The Rice simulations showed normal p53 proteins are compact and easily bind to DNA. “But the mutants have a more open conformation that allows them to interact with other proteins and gives them a higher tendency to produce a condensate,” Kolomeisky said. “It’s possible that future anti-cancer drugs will target the mutants in a way that suppresses the formation of these aggregates and allows wild-type p53 to do its job.” 

Wednesday, January 13, 2021

Women Satisfied With "Going Flat" After Mastectomy

I have "gone flat," as have many women I know. That beguiling descriptor applies to breast cancer patients like me who do not have reconstruction after a mastectomy and therefore have pancake chests. After my bilateral mastectomy in 2015, I didn't want foreign material in my body. I miss my breasts, no doubt about it. In Western culture, breasts can define us as sexual beings; without mine, I feel a tad less desirable. Breasts equal beauty and I have the profile of a pencil. But I can remedy this with bras with prostheses that are comfortable and look natural, so why sign up for additional surgery and a continued need for medical surveillance?

Many other women choose differently, especially those who are younger; I understand and respect the importance of reconstruction for their own mental and physical well-being.

But my decision to “go flat” was right for me, and new research shows I am in good company.

The great majority of women who have decided against reconstruction are comfortable with their choice, according to a study published in the Annals of Surgical Oncology. READ THE STORY HERE.