researchers of the Harvard Medical School (USA) have identified a molecular trigger that activates those cases of the disease that today cannot be explained by the classical model of breast cancer development.
“We have identified what we believe to be the original molecular trigger that initiates a cascade that culminates in the development of breast tumors in a subset of breast cancers that are driven by estrogen,” says the lead investigator of the study published in “Nature.” » Peter Park, Professor of Biomedical Informatics at the Blavatnik Institute.
It is estimated that up to one third of breast cancer cases may arise through this identified mechanism.
The study also shows that the sex hormone estrogen is to blame for this molecular dysfunction because it directly alters a cell’s DNA.
Most, but not all, breast tumors are due to hormonal fluctuations. The prevailing opinion about the role of estrogen in breast cancer is that it acts as a catalyst for cancer growth because it stimulates the division and proliferation of breast tissue, a process that carries the risk of cancer-causing mutations.
The new work, however, shows that estrogen causes damage in a much more direct way.
“Our study demonstrates that estrogen can directly induce genomic rearrangements that lead to cancer, so its role in the development of breast cancer is both a catalyst and a cause,” explains study first author Jake Lee.
Although the work does not have immediate implications for therapy, it could inform the design of tests that can track response to treatment and help doctors detect the return of tumors in patients with a history of certain breast cancers.
trillions of cells
The human body is made up of hundreds of trillions of cells. Most of these cells are constantly dividing and replicating, a process that maintains organ function day after day, throughout life.
With each division, a cell makes a copy of its chromosomes (tightly compressed bundles of DNA) into a new cell. But this process sometimes goes wrong and the DNA can break. In most cases, these DNA breaks are quickly repaired by the molecular machinery that protects the integrity of the genome. However, from time to time, the repair of broken DNA goes awry, causing chromosomes to become misplaced or jumbled within a cell.
Many human cancers arise in this way during cell division, when chromosomes rearrange and wake up latent cancer genes that can trigger tumor growth.
One such chromosome mix-up can occur when a chromosome breaks, and a second copy of the broken chromosome is made before the break is fixed.
Later, in what turns out to be a failed repair attempt, the broken end of one chromosome fuses with the broken end of its sister copy instead of its original partner. The resulting new structure is a misshapen chromosome that malfunctions.
During the next cell division, the misshapen chromosome is stretched between the two emerging daughter cells and the chromosome “bridge” breaks, leaving mangled fragments containing cancer genes to multiply and activate.
Certain human cancers, including some breast tumors, arise when a cell’s chromosomes are rearranged in this way. This malfunction was first described in the 1930s by Barbara McClintockwho won the Nobel Prize in Physiology or Medicine in 1983.
Cancer experts can identify this particular aberration in tumor samples using genomic sequencing. However, a portion of breast cancer cases do not harbor this mutational pattern, which raises the question.
What is causing these tumors?
These were precisely the “cold” cases that intrigued study authors Park and Lee.
In search of answers, they analyzed the genomes of 780 breast cancers obtained from patients diagnosed with the disease. They expected to find the classic chromosome disorder in most of the tumor samples, but many of the tumor cells had no trace of this classic molecular pattern.
Instead of the classic misshapen and incorrectly patched single chromosome, they saw that two chromosomes had fused together, suspiciously close to the “hot spots” where cancer genes are found.
As in McClintock’s model, these rearranged chromosomes had formed bridges, except that, in this case, the bridge contained two different chromosomes. This distinctive pattern was present in a third (244) of the tumors in their analysis.
Lee and Park realized they had stumbled upon a new mechanism by which a “disfigured” chromosome is generated and then fractured to fuel mysterious cases of breast cancer.
When the researchers zoomed in on the hot spots of cancer gene activation, they noted that these areas were close to estrogen-binding areas in DNA.
This offered a clue that estrogen might be involved in some way in the genomic rearrangement that led to the activation of the cancer gene.
Lee and Park followed that lead by conducting experiments with breast cancer cells in a dish. They exposed the cells to estrogen and then used CRISPR gene editing to make cuts in the cells’ DNA.
Estrogen is a more central player in the genesis of cancer because it directly alters the way cells repair their DNA.
As the cells repaired their broken DNA, they started a repair chain that resulted in the same genomic rearrangement that Lee and Park had discovered in their genomic analyses.
It is already known that estrogen stimulates the growth of breast cancer by promoting the proliferation of breast cells. However, the new observations cast this hormone in a different light.
They show that estrogen is a more central player in the genesis of cancer because it directly alters the way cells repair their DNA.
The findings suggest that estrogen-suppressing drugs such as tamoxifen, which are often given to breast cancer patients to prevent a recurrence of the disease, work in a more direct way than simply reducing breast cell proliferation.
“In light of our results, we propose that these drugs may also prevent estrogen from initiating cancer-causing genomic rearrangements in cells, as well as suppress mammary cell proliferation,” says Lee.
The study could lead to better tests for breast cancer. For example, detecting the genomic fingerprint of chromosome rearrangement could alert oncologists that a patient’s disease is returning.adds Lee.
A similar approach to tracking disease relapse and response to treatment is already widely used in cancers harboring critical chromosome translocations, including certain types of leukemias.
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