Bottom Line: Researchers from Memorial Sloan Kettering Cancer Center (MSK) have identified, for the first time, an epigenetic mechanism promoting breast cancer. The team found that inhibition of the PI3K pathway leads to activation of ER-dependent transcription through the epigenetic regulator KMT2D. These findings provide a rationale for epigenetic 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 evidence found in breast cancer.
Journal: “PI3K pathway regulates ER-dependent transcription in breast cancer through the epigenetic regulator KMT2D” appears in the March 24, 2017, issue of Science.
Authors: The study was led by José Baselga, MD, PhD, Physician-in-Chief and Chief Medical Officer, MSK, and Scott Armstrong, MD, PhD, of Dana Farber Cancer Institute. The first author, Eneda Toska, PhD, is a member of the Baselga lab at MSK.
Background: Estrogen-receptor positive (ER-positive) breast cancer is one of the most common types of breast cancer, accounting for 70 percent of all cases. A common oncogenic mutation found in ER-positive breast cancers is in the gene called PIK3CA, which codes for the catalytic subunit of PI3K, a protein that is responsible for coordinating essential cellular functions including growth, survival, and tumorigenesis. Approximately 40 percent of all ER-positive breast cancers have PIK3CA mutations.
PI3K inhibitors have shown antitumor activity in patients with PIK3CA-mutant, ER-positive breast cancer. However, a number of mechanisms of resistance have emerged that could potentially limit their efficacy. Researchers at MSK have been working to understand the early adaptive responses that may mediate resistance to PI3K inhibitors in breast cancer. In this regard, the researchers have observed the presence of a highly uniform tumor response to PI3K inhibitors characterized by an activation of ER-dependent transcription that drives tumor growth and limits the drugs’ therapeutic efficacy.
These findings have paved the way for two large-scale phase III clinical trials (the SANDPIPER and SOLAR-1 studies) currently testing the combination of a PI3K inhibitor with anti-ER therapies in which researchers 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 mechanisms leading to the robust activation of ER upon PI3K inhibition have remained elusive.
Findings: This direct association between KMT2D and the key signaling pathways PI3K and ER provides, for the first time in breast cancer, an indication that this epigenetic regulator is activating ER. Unlike genetic mutations, epigenetic states are in many cases reversible, which means it may be possible to manipulate them with drugs to interfere with tumor-promoting cell processes.
This is the first time that the epigenetic landscape of breast cancer patients treated with PI3K inhibitors has been studied. The discovery of the specific role of KMT2D in the interplay between ER and PI3K signaling provides a rationale for epigenetically informed combination therapies with PI3K inhibitors and anti-ER therapies in this type of breast cancer. In addition, the researchers identified a novel biological mechanism that directly connects the PI3K pathway and its downstream effector, AKT, with epigenetic-based regulation via KMT2D. AKT interacts with and regulates KMT2D function to control ER.
Method: While preliminary clinical trial results are showing promise, researchers at MSK set out to determine the biological mechanisms behind these successes. It is clear that the two most important signaling pathways in breast cancer – ER and PI3K – interact with each other and that it is necessary to target both pathways. But researchers must understand the mechanisms and biology behind this relationship in order to identify new biomarkers and possible treatment options for this patient population.
Researchers used high-throughput epigenetic assays 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 network” is a group of factors that work together 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 activation by the PI3K signaling pathway. The involvement of KMT2D to activate ER was confirmed through key patient biopsy samples. Further work confirmed that if KMT2D was removed, the ER activation that had previously been seen when the PI3K pathway was inhibited was no longer happening. In mice bearing tumors, the authors confirmed that genetically removing KMT2D and inhibiting the PI3K pathway achieved the highest tumor shrinkage than either alone.
Author Comments: “This work is a perfect example of how clinical observations drive fundamental research. We are able to ask relevant questions and form hypotheses based on real people and in real time,” explained Dr. Baselga. “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 signaling pathways – ER and PI3K – will allow us to explore new therapeutic targets and combination treatment approaches for this patient population.”
“Over the past few years, we have learned that epigenetic mechanisms play a critical role in the initiation, development, and progression of many types of cancer, including lymphoma and some leukemias, although we have never seen it in breast cancer,” explained Dr. Toska. “Now that we have identified a new mechanism directly connecting an oncogenic signaling pathway with epigenetic regulation in ER-positive breast cancer, we can explore the possibility of targeted and personalized therapies with a more limited chance of resistance in this setting.”