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Genetic Engineering & Biotechnology News | GENengnews.com | APRIL 15, 2017 | 17 While the impact of epigenetics on various cancers has been postulated to be significant, direct evidence of its influence on tumor for- mation and progression for breast cancer was elusive. However, a team of researchers led by scientists at Memorial Sloan-Kettering Cancer Center (MSK) have identified, for the first time, an epigenetic mechanism promot- ing breast cancer. The findings from this study were released in the journal Science, "PI3K pathway regulates ER-dependent transcrip- tion in breast cancer through the epigenetic regulator KMT2D." In the current study, the researchers found that inhibition of the PI3K pathway led to activation of ER-dependent transcription through the epigenetic regulator KMT2D. These findings provide a rationale for epi- genetic therapy in patients with PIK3CA- mutant, ER-positive breast cancer. While epigenetic factors have been known to play an important role in various cancers, such as leukemia and lymphoma, this is the first evi- dence found in breast cancer. "This work is a perfect example of how clinical observations drive fundamental research. We are able to ask relevant ques- tions and form hypotheses based on real people and in real time," explained senior study investigator Jose Baselga M.D., Ph.D., physician in chief and CMO at MSK. "The discovery of a link between epigenetics and the PI3K pathway in breast cancer is another important piece of the puzzle. Understanding the mechanisms of the two important signal- ing pathways—ER and PI3K—will allow us to explore new therapeutic targets and com- bination treatment approaches for this pa- tient population." Estrogen-receptor positive (ER-positive) breast cancer is one of the most common types of breast cancer, accounting for 70% of all cases. A common oncogenic mutation found in ER-positive breast cancers is in the gene called PIK3CA, which encodes the catalytic subunit of PI3K, a kinase that is responsible for coordinating essential cellular functions including growth, survival, and tumorigenesis. Approximately 40% of all ER-positive breast cancers have PIK3CA mutations. PI3K inhibitors have shown to have ef- fective antitumor activity in patients with PIK3CA-mutant, ER-positive breast cancer. However, some mechanisms of resistance have recently emerged that could potentially limit their efficacy. Researchers have been working to understand the early adaptive re- sponses that may mediate resistance to PI3K inhibitors in breast cancer. Scientists have ob- served that the presence of a highly uniform tumor response to PI3K inhibitors character- ized by an activation of ER-dependent tran- scription that drives tumor growth and limits the drugs' therapeutic efficacy. These findings have paved the way for two large-scale Phase III clinical trials cur- rently testing the combination of a PI3K in- hibitor with anti-ER therapies, in which re- searchers have observed encouraging clinical activity. If the trials continue to show positive results, the combined inhibition of PI3K and ER could become the new standard of care for metastatic PIK3CA-mutant, ER-positive tumors. However, the underlying mecha- nisms leading to the robust activation of ER upon PI3K inhibition have remained elusive. While preliminary clinical trial results are showing promise, the MSK researchers set out to determine the biological mechanisms behind these successes. Using high-through- put epigenetic assays, the scientists were able to study for the first time the global epigenetic landscape of breast cancer cells from patients treated with PI3K inhibitors in clinical trials at MSK. Knowing that ER, as a transcription factor, regulates genes, researchers utilized high-throughput assays and found that it works in cooperation with other transcription factors. This "transcription factor regulatory net- work" is a group of factors that work togeth- er to mediate growth and require epigenetic marks to do so. These marks are catalyzed by an epigenetic regulator called KMT2D. KMT2D is important for cell maintenance, differentiation, and growth. With the assays, the researchers identified KMT2D as the key determinant of ER acti- vation by the PI3K signaling pathway. The involvement of KMT2D to activate ER was confirmed through key patient biopsy sam- ples. Further work confirmed that if KMT2D was removed, the ER activation that had pre- viously been seen when the PI3K pathway was inhibited was no longer happening. In mice bearing tumors, the authors confirmed that genetically removing KMT2D and inhib- iting the PI3K pathway achieved higher tumor shrinkage than either thereapy alone. "Over the past few years, we have learned that epigenetic mechanisms play a critical role in the initiation, development, and pro- gression of many types of cancer, including lymphoma and some leukemias, although we have never seen it in breast cancer," noted lead study investigator Eneda Toska, Ph.D., a research fellow in Dr. Baselga's laboratory. "Now that we have identified a new mecha- nism directly connecting an oncogenic signal- ing pathway with epigenetic regulation in ER-positive breast cancer, we can explore the possibility of targeted and personalized ther- apies with a more limited chance of resistance in this setting." © 2017 MaxCyte, Inc. All Rights Reserved. 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