Estrogen Directly Induce Genomic Rearrangements That Lead To Cancer

Researchers at Harvard Medical School have discovered the molecular sparkplug that ignites cases of the disease, which is now unaccounted for by the traditional model of breast-cancer development.

This discovery may turn out to be a long-missing piece in the breast cancer puzzle.

Nature will publish a report on the team’s findings on May 17.

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

According to the researchers, the newly discovered mechanism may be responsible for up to one-third of breast cancer cases.

Because it directly modifies a cell’s DNA, the study also demonstrates that the sex hormone estrogen is the source of this cellular malfunction.

Hormonal variations are the cause of the majority of breast cancers, albeit not all.

The general consensus on estrogen’s role in breast cancer is that it serves as a catalyst for cancer growth by encouraging breast tissue division and proliferation, a process that raises the possibility of cancer-causing mutations.

The latest research, however, demonstrates that estrogen causes trouble in a much more direct way.

“Our work demonstrates that estrogen can directly induce genomic rearrangements that lead to cancer, so its role in the development of breast cancer is both that of a catalyst and a cause,” said study’s first author Jake Lee, a former research fellow in the Park lab who is currently a medical oncology fellow at Memorial Sloan Kettering Cancer Center.

Despite the fact that the research has no immediate therapeutic consequences, it may help in the development of tests that monitor treatment response and may aid medical professionals in identifying tumor recurrence in people with a history of particular breast malignancies.

Estrogen playing a new function in breast cancer?

Zooming in on the hotspots of cancer-gene activation, the researchers observed that these regions were oddly close to estrogen-binding regions on the DNA.

When an estrogen-stimulated cell moves toward a certain region of the genome, estrogen receptors are known to bind there.

These estrogen-binding sites were typically located close to the regions where the early DNA breaks occurred, the researchers discovered.

This provided a strong indication that estrogen might be connected to the genomic reorganization that led to the activation of cancer-related genes.

Lee and Park carried out tests on breast cancer cells in a dish in response to that hint. They made DNA alterations in the cells after estrogen exposure using CRISPR gene editing.

The genomic rearrangement Lee and Park had uncovered in their genomic analysis was produced as a result of the cells’ efforts to repair their damaged DNA.

By encouraging the growth of breast cells, estrogen is already known to promote the spread of breast cancer. However, the latest findings provide a different picture of this hormone.

They demonstrate that estrogen, which directly affects how cells repair their DNA, has a more significant role in the development of cancer.

The results show that estrogen-suppressing medications, like tamoxifen, which are frequently prescribed to breast cancer patients to prevent disease recurrence, function more directly than just by slowing breast cell proliferation.

In light of our findings, we suggest that in addition to inhibiting mammary cell proliferation, these medications may also prevent estrogen from starting cancer-causing genetic rearrangements in the cells, Lee said.

The study might result in enhanced breast cancer screening. For instance, doctors may be informed if a patient’s cancer is relapsing if their genomic fingerprint of the chromosome rearrangement is detected, according to Lee. read full article

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