Breast Cancer Origins Discovered

Harvard Medical School researchers have uncovered the molecular sparkplug that ignites cases of breast cancer that are now unexplained by the conventional model of breast cancer development, which could be a long-missing piece in the puzzle of breast cancer.

“We have identified what we believe is the original molecular trigger that initiates a cascade culminating in breast tumor development in a subset of breast cancers that are driven by estrogen,” said study senior investigator Peter Park, professor of Biomedical Informatics in the Blavatnik Institute at HMS.

According to the researchers, the newly discovered mechanism could account for up to one-third of all breast cancer cases.

The study also demonstrates that the sex hormone estrogen is to blame for this molecular malfunction since it directly affects the DNA of cells.

Hormonal changes generate the majority, but not all, breast cancers. The widely held belief about estrogen’s role in breast cancer is that it acts as a catalyst for cancer growth by stimulating the division and proliferation of breast tissue, a process that increases the likelihood of cancer-causing mutations. The latest research, on the other hand, demonstrates that estrogen causes havoc in a far more direct way.

“Our work demonstrates that estrogen can directly induce genomic rearrangements that lead to cancer, so its role in breast cancer development is both that of 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.

Although the findings have no immediate consequences for therapy, they may help clinicians create tests to evaluate treatment response and detect tumor recurrence in people with a history of specific breast malignancies.

The formation of a cancer cell

Hundreds of billions of cells make up the human body. Most of these cells are constantly dividing and duplicating, sustaining organ function day after day, spanning a lifetime.

A cell divides by replicating its chromosomes — bundles of densely compacted DNA — into a new cell. However, this process can go wrong and cause DNA to break. In most circumstances, the molecular machinery that protects the genome’s integrity quickly repairs these DNA breaks. However, every now and then, the repair of broken DNA fails, resulting in chromosomes being displaced or scrambled within a cell.

Many human malignancies develop in this way during cell division, when chromosomes are altered and dormant cancer genes that can cause tumor growth are activated.

A chromosomal scramble can occur when a chromosome breaks and a second copy of the fractured chromosome is formed before the break is repaired.

The broken end of one chromosome is then joined to the broken end of its sister copy rather than to its original partner, resulting in a botched repair effort. The end outcome is a deformed, dysfunctional chromosome.

During the next cell division, the deformed chromosome is stretched between the two developing daughter cells, and the chromosome “bridge” breaks, allowing cancer genes to multiply and become active.

When a cell’s chromosomes are altered in this manner, certain human malignancies, including certain breast tumors, develop. Barbara McClintock, who won the Nobel Prize in Physiology or Medicine in 1983, initially characterized this dysfunction in the 1930s.

Using genetic sequencing, cancer professionals can frequently discover this specific abnormality in tumor samples. However, a fraction of breast cancer cases lack this mutational pattern, asking the question, “What causes these tumors?”

These were the “cold” examples that piqued the interest of study authors Park and Lee. In search of solutions, they examined the genomes of 780 breast tumors taken from patients with the condition. They expected to find the characteristic chromosomal disorder in the majority of the tumor samples, however many of the tumor cells lacked this classic molecular pattern.

Instead of the typical deformed and poorly patched-up single chromosome, they discovered that two chromosomes had fused, eerily near “hot spots” where cancer genes are found.

These altered chromosomes had produced bridges, much like in McClintock’s model, only this time the bridge contained two distinct chromosomes. This specific pattern was found in one-third (244) of the tumors studied.

Lee and Park recognized they had discovered a novel process for the generation of “disfigured” chromosomes, which are then shattered to drive the mystery breast cancer instances.

Estrogen’s new involvement in breast cancer?
When the researchers focused their attention on the hotspots of cancer-gene activation, they observed that they were strangely close to estrogen-binding sites on the DNA.

When a cell is activated by estrogen, estrogen receptors are known to bind to certain areas of the genome. The estrogen-binding sites were typically located around the areas where the early DNA breaks occurred, according to the researchers.

This provided a strong indication that estrogen was involved in the genomic reshuffling that resulted in cancer-gene activation.

Lee and Park followed up on that lead by doing experiments in a dish with breast cancer cells. They exposed the cells to estrogen before using CRISPR gene editing to generate DNA cuts in the cells.

As the cells repaired their broken DNA, they started a repair chain that culminated in the identical genomic rearrangement found by Lee and Park in their genomic analysis.

Estrogen is already known to promote breast cell proliferation, which aids in the growth of breast cancer. The current findings, however, cast this hormone in a new light.

They demonstrate that estrogen is a more important player in cancer genesis because it directly affects how cells repair their DNA.

The findings suggest that estrogen-suppressing medications like tamoxifen, which is commonly given to breast cancer patients to prevent disease recurrence, function in a more direct way than just lowering breast cell proliferation.

“In light of our results, we propose that these drugs may also prevent estrogen from initiating cancer-causing genomic rearrangements in the cells, in addition to suppressing mammary cell proliferation,” Lee said.

The study could lead to improved breast cancer testing. For instance, detecting the genomic fingerprint of the chromosome rearrangement could alert oncologists that a patient’s disease is coming back, Lee said.

A comparable method for tracking disease relapse and treatment response is already commonly employed in tumors with significant chromosomal translocations, such as certain forms of leukemia.

The study, in general, highlights the importance of DNA sequencing and rigorous data analysis in understanding the biology of cancer formation, according to the researchers.

“It all started with a single observation. We noticed that the complex pattern of mutations that we see in genome sequencing data cannot be explained by the textbook model,” Park said. “But now that we’ve put the jigsaw puzzle together, the patterns all make sense in light of the new model. This is immensely gratifying.”

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