Era of Hope 2011 Investigator Vignette

Title: Maternal Consumption of Omega-3 Reduces Breast Cancer in Offspring

Investigator: W. Elaine Hardman, Ph.D., Marshall University School of Medicine
Philippe Georgel, Ph.D., Marshall University School of Medicine

Hardman: The focus of my research is to try to develop strategies to help prevent breast cancer. Probably 30 – 60 percent or 70 percent of all cancers can be prevented if we made some diet or lifestyle changes. I focus on Omega 3 fatty acids. In this grant, we’re looking at the epigenetic events that tell you why maternal consumption of a dietary change can alter breast cancer risk in the offspring even when the offspring haven’t seen the dietary change since they time they were weaned. In the first grant that led up to this, we found that if the mother mouse only was consuming a small amount of Omega 3 fat in her diet in the form of canola oil—we removed some of the corn oil from the diet and put in canola oil then the babies, even though the babies never saw the canola oil again after they were weaned, had 50% less risk for developing breast cancer. And if they did develop a breast cancer, the tumor grew at only one-half the rate.

Now we show that here; at 130 days, the baby mice had less than half the number of tumors as the group that didn’t see any canola oil in their background. Even at 170 days, there was still a significantly less tumor weight in the—the baby mice whose mothers consumed canola oil. And if the mice developed a tumor, then the growth rate was only about half as much as the growth rate of tumors in mice that did not have canola oil in their background.

We saw at 130 days of age that there was significant changes in gene expression of a number of genes that are important for promotion of breast cancer. Now remember these mice hadn’t seen the dietary change since they were weaned at 21 days old. So this tells us that there must have been some kind of lasting change to—that influenced gene expression and we call this imprinting. So that’s where my colleague Dr. Georgel comes in; he’s an expert at looking at imprinting changes, methylation changes, and other changes in the chromatin structure, the structure of the DNA that defines how genes are going to be expressed.

Georgel: So we have to explain how the changes in gene expression from the mother are transmitted to the offspring is going to be explained without having any mutations and how that particular event is going to be spread from one generation to the next.

The genes are going to be the same. But the way they are going to be decorated is quite different and that decoration can stay for a long-term and leading to the imprinting, something that can be passed hopefully to the next generation as well. We’re looking at the first generation but we believe that the second generation would be affected as well by the change in diet that the mother has underwent.

In this particular panel here, we looked at a profile of gene expression in the context of Omega 3 fatty acid diet for the mother versus Omega 6 fatty acid mostly for the current cohort. And we found that there are several genes that have been either up-regulated, turned on, or down-regulated, turned off partially. So the way you can do that is by basically changing the recruitment of protein that goes and binds to regions that regulate the expression of those genes. And that can be modulated by protein binding to the DNA directly but the DNA in the cell is packaged in a way that involves other proteins called histones. And those histones can be also modified themselves. And they actually act as little flags for other proteins to bind and act as co-activator to turn genes on or co-repressor to turn genes off. So we looked at different of those modifications that can happen on those proteins called histones and see how the change in diet would affect those modifications themselves, therefore the protein that can bind to the genes and turn on or turn off the gene that we identified as being affected by the diet.

We found two of them, one in this one H4 Lysine 16 Isolation. It’s a marker for active genes. We also found that the diet changes a marker for repressed genes. So what we have now is a global idea of how a change in diet can affect markers for activation of genes or repression of genes. Now what we need to do is assign those changes to specific genes, so we’re going to do a map of all those changes and align them with the genome, with the gene that we have identified as being controlled or modified by the change in diet.

DNA-related events are not everything—that we can change the gene expression profile by changing something that has nothing to do with the DNA sequence. But the most important thing I think is that we can go for those changes through very simple changes in diet. If you look at it, it’s pretty simple; I mean you go from corn oil to canola oil and you reduce the incidence of breast cancer in the offspring by 50%. You reduce the tumor growth rate by a significant value as well. And it’s not something that’s going to just you know—mutation everywhere; it’s not going to have the deleterious effect on the DNA. You’re not messing up with any of the other genes and you are going to create something that’s going to be going from one generation to the next, so it’s a long-term effect.

So by being able to match diet—maternal diet to epigenetic changes we are creating basically a new field in the—for breast cancer. People are going to look more and more at those different levels of regulation that you can see. It’s no longer just DNA does everything. It’s DNA plus a protein that can associate with it; it’s DNA plus a protein associated with it, plus how they are going to be modified, and all that with a simple change—I found that quite interesting actually.