Wednesday, November 13, 2024

How Even One Faulty Copy of the BRCA1 Gene Can Fuel Breast Cancer

Good news! Cancer is history (soon)!

Caveat: I did not read the entire, long article.

"At a glance:
  • The findings suggest the dominant “two-hit” hypothesis of cancer development may not tell the full story behind how cancer arises.
  • Study identifies cellular changes that prime cancer-related genes for action and render cells vulnerable to tumor growth.
  • The findings can inform new treatments that block the priming effect to prevent breast cancer formation.
...
To answer this question, the researchers compared mammary gland cells from both groups of mice. The cells of the group with a single defective copy of the BRCA1 gene showed telltale changes in the organization and packaging of DNA that render certain cancer-promoting genes more readily accessible. Specifically, these cells contained alterations in the structure and organization of chromatin, the material that helps package and maintain DNA in a cell’s nucleus.

Some of these changes were reminiscent of alterations seen in cells that had already become cancerous. For instance, cells with a single defective BRCA1 copy had chromatin changes that rendered a gene called WNT10A more prone to activation. This gene is known for its roles in regulating cell division and growth. Overactivity in this gene can lead to aberrant cell growth, which promotes cancer. Notably, the chromatin structure around the WNT10A gene became more open and accessible for transcription factors such as JUN to dock and activate its expression, thus leading to a faster ignition of tumor development. ..."

From the abstract:
"Germline BRCA1 mutation carriers face a high breast cancer risk; however, the underlying mechanisms for this risk are not completely understood. Using a new genetically engineered mouse model of germline Brca1 heterozygosity, we demonstrate that early tumor onset in a Brca1 heterozygous background cannot be fully explained by the conventional ‘two-hit’ hypothesis, suggesting the existence of inherent tumor-promoting alterations in the Brca1 heterozygous state. Single-cell RNA sequencing and assay for transposase-accessible chromatin with sequencing analyses uncover a unique set of differentially accessible chromatin regions in ostensibly normal Brca1 heterozygous mammary epithelial cells, distinct from wild-type cells and partially mimicking the chromatin and RNA-level changes in tumor cells. Transcription factor analyses identify loss of ELF5 and gain of AP-1 sites in these epigenetically primed regions; in vivo experiments further implicate AP-1 and Wnt10a as strong promoters of Brca1-related breast cancer. These findings reveal a previously unappreciated epigenetic effect of Brca1 haploinsufficiency in accelerating tumorigenesis, advancing our mechanistic understanding and informing potential therapeutic strategies."

How Even One Faulty Copy of the BRCA1 Gene Can Fuel Breast Cancer | Harvard Medical School "Research adds a new twist to prevailing two-hit model, offering new insight for prevention"





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