In what may prove to be a missing piece in the puzzle of breast cancerHarvard Medical School researchers have identified the molecular factor that causes cancer.
The results of research were published in the scientific journal natures.
Breast cancer some details on the new research
“We have identified what we believe is the original molecular trigger that initiates a cascade that culminates in breast cancer development in a subset of breast cancers that are estrogen-driven,” said study senior investigator Peter Park, professor of biomedical informatics at the Blavatnik Institute at HMS.
The researchers said that up to a third of breast cancer cases can arise through the newly identified mechanism. The study also shows that the sex hormone estrogen is the culprit for this molecular dysfunction because it directly alters a cell’s DNA.
Most, though not all breast cancers are fueled by hormonal fluctuations. The prevailing view on the role of estrogen in breast cancer is that it acts as a catalyst for cancer growth because it stimulates breast tissue to divide and proliferate, a process that carries the risk of cancer-causing mutations. The new work, however, shows that estrogen causes harm in a much more direct way.
“Our work demonstrates that estrogen can directly induce genomic rearrangements leading to cancer, so its role in the development of breast cancer is that of both a catalyst and a cause,” said study first author Jake Lee, a former research fellow in the Park lab who is now a medical oncology fellow at Memorial Sloan Kettering Cancer Center.
While the work has no immediate implications for therapy, it could inform the design of tests that can monitor response to treatment and could help doctors detect tumors returning in patients with a history of certain breast cancers. The human body is made up of hundreds of trillions of cells. Most of these cells are constantly dividing and replicating, a process that sustains organ function day after day, throughout life.
With each division, a cell makes a copy of its chromosomes, tightly packed bundles of DNA, in a new cell. But this process sometimes goes wrong and DNA can break. In most cases, these DNA breaks are quickly repaired by the molecular machinery that protects the integrity of the genome. However, occasionally, the repair of broken DNA fails, causing chromosomes to become lost or mixed up within a cell.
Many human cancers arise this way during cell division, when chromosomes are rearranged and wake up dormant cancer genes that can trigger tumor growth. One such chromosome scramble can occur when a chromosome breaks and a second copy of the broken chromosome is made before the break is repaired.
Then, in what ends up being a failed repair attempt, the broken end of a chromosome is fused with the broken end of its sister copy rather than its original partner. The resulting new structure is a malformed and malfunctioning chromosome.
During the subsequent cell division, the misshapen chromosome is stretched between the two emerging daughter cells and the chromosomal “bridge” breaks, leaving behind shattered fragments that contain the cancer genes to multiply and activate.
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Cancer experts can often identify this particular aberration in tumor samples using genomic sequencing. However, a portion of breast cancer cases do not harbor this mutational pattern, begging the question: what is causing these tumors?
These were the “cold” cases that intrigued study authors Park and Lee. Looking for answers, they analyzed the genomes of 780 breast cancers obtained from patients diagnosed with the disease. They expected to find the classic chromosomal disorder in most of the tumor samples, but many of the tumor cells bore no trace of this classic molecular pattern.
Instead of the classic misshapen and improperly patched single chromosome, they saw that two chromosomes had fused, suspiciously near ‘hot spots’ where cancer genes are found.
Just as in McClintock’s model, these rearranged chromosomes had formed bridges, except in this case the bridge contained two different chromosomes. This distinctive pattern was present in one 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 cancer gene activation hotspots, they noticed that these areas were curiously close to estrogen-binding areas on the DNA.
Estrogen receptors are known to bind to certain regions of the genome when a cell is stimulated by estrogen. The researchers found that these estrogen binding sites were often close to where the first DNA breaks occurred.
This offered a strong hint that estrogen might somehow be involved in the genomic shuffling that gave rise to cancer gene activation.
Lee and Park followed up on 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 cut the cells’ DNA.
When the cells repaired their broken DNA, they started a chain of repair that led to the same genomic rearrangement that Lee and Park discovered in their genomic analyses.
It is already known that estrogen fuels the growth of breast cancer by promoting the proliferation of breast cells. However, the new observations cast this hormone in a different light. Research has highlighted 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, often given to breast cancer patients to prevent disease recurrence, act more directly than simply reducing breast cell proliferation.
“In light of our findings, we propose that these drugs may also prevent estrogen from initiating cancer-causing genomic rearrangements in cells, as well as suppress breast cell proliferation,” Lee said.
The study could lead to improved breast cancer testing. For example, detecting the genomic fingerprint of chromosome rearrangement could alert oncologists that a patient’s disease is returning, Lee said.
A similar approach to monitor disease relapse and treatment response is already widely used in cancers harboring critical chromosomal translocations, including some types of leukaemias. More broadly, the work emphasizes the value of DNA sequencing and careful data analysis for gaining insight into the developmental biology of cancer, the researchers said.
“It all started with a single observation.
“We noticed that the complex pattern of mutations we see in genome sequencing data cannot be explained by the textbook model,” Park said. “But now that we’ve put the puzzle together, all the patterns make sense in light of the new model. This is immensely gratifying.”
In Italy, according to the Ministry of Health: “The numbers of cancer in Italy 2022 confirm that breast cancer is the most diagnosed malignancy in women, in which approx one in three malignancies (30%) is breast cancer (The numbers of cancer in Italy 2020).
The 2022 report estimates in Italy for the year 2022 about 55,700 new cancer diagnoses in women, with an increase of 0.5% compared to 2020.
Mortality for the 2021 is estimated at 12,500 deaths. The 5-year net survival after diagnosis is estimated by the report to be 88%. The probability of living another 4 years, conditioned on having passed the first year after diagnosis, is indicated as 91%.
According to ISTAT data in 2018 the breast cancer represented, with 13,076 deaths, the leading cause of cancer death in women.
Since the end of the 1990s, there has been a continuous downward trend in breast cancer mortality (-0.8%/year), attributable to a greater diffusion of early diagnosis programs (therefore to diagnostic anticipation) and also to therapeutic progress” .
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