For the first time, we have almost complete understanding of the genetic changes that drive cancer, and we have begun to understand the role that epigenetic changes play in cancer progression….— Myles Brown, MD
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The field of epigenetics emerged in the 1990s and has been described with somewhat variable meanings. In 2008, a meeting at the Cold Spring Harbor laboratory arrived at a definition of epigenetics by consensus: “A stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence.” Since its emergence, epigenetics has become an increasingly interesting area of research among the oncology community.
To shed light on the current state of epigenetic research, The ASCO Post spoke with Myles Brown, MD, Professor of Medicine and Director of the Center for Functional Cancer Epigenetics at the Dana-Farber Cancer Institute and Harvard Medical School. He is a medical oncologist, and over the past many years, his work has focused on understanding the role of transactivation by steroid hormone receptors and epigenetic changes, primarily in breast and prostate cancers.
Epigenetics in Cancer Research
Please shed some light on the role of epigenetics in cancer research.
The potential importance of epigenetically defined cells of origin have become clear in determining meaningful dependencies across different cancer types. So, in our work, we think about it in terms of, for instance, estrogen stimulation in the growth of certain breast cells. That’s true in the normal breast and also in breast cancer. And this lineage dependency, which of course is determined epigenetically, makes the majority of breast cancers dependent on estrogens for their growth. We know that many of the differences between different cancer types are in some ways remnants of the epigenetic history of that tissue. We believe that changes in the functions of factors that play critical roles in the normal development play aberrant roles in cancer and are potential therapeutic targets.
While we know that cancer is primarily driven by somatic genetic changes, that is, mutations in key genes such as tumor suppressors and oncogenes, more recently we’ve come to appreciate that nonmutational changes can also play important roles in carcinogenesis often linking nonmutagenic environmental exposures to cancer risk and progression.
Environmental Exposures
Do we have clear knowledge of external factors such as lifestyle that are involved in epigenetics?
There are a lot of ideas—but not a lot of proof—that environmental exposures, both the external environment such as chemical toxins and the internal environment such as hormones, can play an important role in cancer risk and progression. We study the effect of steroid hormones in breast and prostate cancers.
For instance, a woman’s reproductive history plays a major role in determining her risk of developing breast cancer. The working hypothesis is that the effects of these factors are driven primarily through nonmutational mechanisms. There are reasons to believe that these risk exposures may increase the number of mammary progenitor and stem cells, which are thought to be the targets of mutational changes that lead to cancer. Therefore, the changes in risks may be related to the changes in the size of the population of potential cells of origin of the cancer that determines a person’s risk.
For example, in women, is that an earlier age of menarche puts them at an increased risk for developing breast cancer decades later. So, the theory is that the change in timing of menarche somehow alters the differentiation state of the normal breast, putting more cells at risk for eventual mutational events that become cancer.
Center for Functional Cancer Epigenetics
Please give our readers an overview of the Center for Functional Cancer Epigenetics.
About 5 years ago, my long-time collaborator Shirley Liu, PhD, and I started the Center to further research into the role played by epigenetic changes in modifying cancer progression and to identify therapeutic vulnerabilities in cancer related to epigenetic changes. We came to study epigenetics starting from our work on the impact of chromatin biology on transcriptional regulation. It has become increasingly clear over the past 20 years that the post-translational modification of histones in chromatin plays an important role in facilitating the action of transcription factors to determine the epigenetic state of a cell. Our center also collaborates with colleagues at Dana-Farber, Harvard Medical School, and beyond to help facilitate their work, looking at different aspects of cancer epigenetics by providing computational and research platforms that they can access through our center.
Enzyme Inhibitors in Development
How can the work you and others are doing in epigenetics translate into cancer therapies?
Over the past decade, the cancer genome studies, in which large numbers of different cancers of different cell types have been sequenced, have revealed that genetic mutations in the enzymes play an important role in establishing and maintaining the genetic identity of the cells that are themselves often mutated. Some of the most frequent mutations we see in cancer turn out to be the mutations in the very proteins that write, erase, or read histone modifications This tells us that those mutations in altering the epigenetic state of the cells likely have an important effect on cancer progression and may be therapeutic targets. In fact, several pharmaceutical and biotech companies are actively developing inhibitors of these proteins, some of which are already being tested clinically, including trials in non-Hodgkin lymphoma and other cancer types.
Unprecedented Progress
Would you like to share some closing comments?
I was trained as a medical oncologist in the late 1980s, and over the past 30 plus years, the progress we’ve seen is unprecedented. For the first time, we have almost complete understanding of the genetic changes that drive cancer and have begun to understand the role that epigenetic changes play in cancer progression. The long hypothesized role of the immune system in controlling cancer has finally become a therapeutic reality, and there is significant interest in using drugs to manipulate the epigenetic state of cancers, so we can also increase their susceptibility to the effects of immunotherapy. I think we’ve arrived at a point where our scientific knowledge can translate into major therapeutic advances at an ever-increasing rate, provided there is a continued robust investment in cancer research. ■
Disclosure: Dr. Brown reported no potential conflicts of interest.
