Chromosome Alterations Contribute to Drug Resistance in ER+ Breast Cancer

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Estrogen receptor positive (ER+) breast cancer accounts for 70% of all diagnoses of the disease. When cancer cells with this particular mutation become resistant to hormone therapy, it is very problematic for patients, in that the cancer cells no longer respond to treatment. Recent studies have shown that epigenetic interactions that occur in the DNA of breast cancer cells are responsible for this resistance, and reversing or preventing these interactions has the potential to reduce breast cancer relapse.

Professor Susan Clark and colleagues at the Garvan Institute of Medical Research showed that the 3D structure of DNA is ‘rewired’ in hormone resistant ER+ breast cancers, altering normal gene activation and repression in the cells. The researchers published their findings in the journal Nature Communications.

“For the first time, we’ve revealed crucial 3D DNA interactions that are linked to whether or not a breast cancer is sensitive to hormone therapy,” says senior author Professor Clark.  “Understanding this process reveals new insights into how ER+ cancers evade hormone therapy, allowing them to grow uncontrolled.”

The estrogen hormone can be an inadvertent driver of cancer growth – ER+ breast cancers grow in response to estrogen exposure to tumor cells. Treatment that blocks the patient from producing and thus exposing estrogen to these cells, known as hormone therapy, is often successful at stopping cancer growth and reducing relapse. However, many breast cancers become resistant to hormone therapy over time.

“Treatment resistance is a significant health problem that leads to a third of all ER+ breast cancer patients on hormone therapy relapsing within 15 years,” says the study’s first author Dr. Joanna Achinger-Kawecka.

She continues that this research group was interested in epigenetic changes to DNA, as it is that layer of instructions that organizes and regulates DNA’s activity, and also underpins the development of hormone resistance in breast cancer.  “Understanding these fundamental changes may help guide development of future treatments that either prevent resistance from developing, or reverse it once it has occurred.”

 The researchers managed to show that 3D chromatin interactions both within and between topologically associating domains (TADs) frequently change in ER+ endocrine-resistant breast cancer cells.

Using chromosome conformation capture, a cutting-edge technique that provides a snapshot of how DNA is arranged and interacts in three dimensions in the cell, the researchers compared different ER+ breast cancer cells that were either sensitive or resistant to hormone treatment.

“Between breast cancer cells that were still sensitive to hormone treatment and those that had developed resistance, we saw significant changes in 3D interactions of DNA regions that control gene activation. Including at genes that control the estrogen receptor levels in the cells,” says Dr Achinger-Kawecka.

“Further, we found that this 3D ‘rewiring’ occurred at DNA regions that were methylated, which is an epigenetic change that the team has already linked to hormone resistance.”

The researchers say that the altered DNA methylation at critical regulatory regions may explain how the 3D structure of DNA is rewired as a cancer cell develops hormone resistance, allowing the cancer to better evade treatment.

Ectopic chromatin interactions are preferentially enriched at active enhancers, promoters and ER binding sites.  They are often associated with altered expression of ER-regulated genes, consistent with dynamic remodeling of ER pathways accompanying the development of endocrine resistance.

 “Cancer cells are always trying to outsmart therapy and it only takes one cell to evolve a different way to bypass a drug to cause a relapse in cancer,” says Professor Clark. “Our study shows us just how much impact a change in the epigenome can have on cancer cell behavior.”

The researchers say the next step is to investigate whether epigenetic changes could be reversed to stop hormone resistance, using existing drugs that are already in clinical trials for other cancers, including lung and colorectal cancer.  As the research is suggesting it is the chromosome remodeling that leads to the development of resistance, preventing chromosomal interactions would likely prevent it.

“Once ER+ breast cancer patients become resistant to hormone therapy, it is more difficult to treat,” says Professor Clark. “We hope our research will help lead to combination treatments that allow women to take hormone therapy for longer, giving them better clinical outcomes.”

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