Wednesday, September 7, 2011
A San Diego cancer biologist will explain how a late night in a Salk Institute laboratory lead to a eureka moment with a gene connected to breast cancer.
Doctors at the Salk Institute are announcing a breakthrough in Breast Cancer research. The finding relates specifically to women who have a genetic risk of developing breast cancer. The research may lead to better tests and ultimately better treatments.
Dr. Gerald Pao, is a cancer biologist at the Salk Institute and co-author of a study of the BRCA1 gene published in the current issue of the journal Nature.
CAVANAUGH: Researchers at Salk institute in San Diego announce a major step forward in understanding breast cancer.
I'm Maureen Cavanaugh, it's Wednesday, September†7th. Our top story on Midday Edition, doctors at Salk institute are announcing a break through in breast cancer retch. Finding relates specifically to women who have a genetic risk of developing breast cancer. The research may lead to better tests and treatments. My guest, doctor Gerald Pao is a cancer biologist at the Salk institute. Welcome.
PAO: Thank you for having me here.
CAVANAUGH: Now, there's a lot about this research break through that's a lot difficult for a layperson to understand so I'm going to ask you to help us through it a bit, okay? First of all, what specific gene did you study?
PAO: The gene we're studying is called BRCA one. It was first discovered in 1994, and the consequence of it was determined but it was not particularly informative at that point because the gene itself basically had no features that were recognizable. But this gene whenever it's mutated, which mean us have a defective copy of it, predisposes you to breast cancer. By the age of 70 in families that are particularly susceptible, you have a 99% of developing breast cancer at that age.
CAVANAUGH: Does every woman have the BRCA one gene?
PAO: Everybody has the gene, but not everybody has the defect. If you're predisposed to breast cancer, then you have one defective copy of that gene, and sometime in your life, one of the cells in your breast or ovaries produces a second copy, then you start the development of breast cancer.
CAVANAUGH: Am I understanding it directly that a lot of your research actually discovered how this particular gene stops cancer when it's actually working normally?
PAO: Yeah, exactly. Peaceful when you're trying to figure out is why does this BRCA1 gene prevent the formation of breast cancer. And the goal of the study was basically what does it do at the molecular level, what does it interact with, what are its friends, and what does it do to stop cancer from happening?
CAVANAUGH: This stove is particularly important as you said for women who have hereditary terms. Breast and ovarian cancer. What percentage of cancer is genetic?
PAO: The total number of incidents of cancer in the United States is about 230,000†cases according to the cancer society are per year. And 10% of those are of the inherited form, which is like BRCA 1 or 2. And roughly half of those are BRCA one and half are BRCA2.
CAVANAUGH: So women who are at risk of genetic breast cancer are already now advised to get early screenings. How does what you discovered help that?
PAO: Well, the thing is, we have to understand it in the first place. And if we don't understand it, you cannot do anything about it. So one of the thing this is we have done is discovered what is the first sign of loss of BRCA1? So we have found that certain genes get turned on. And these are not traditional genes. But these genes that get turned on, we're trying to find ways to devise a way through a blood test, you can actually test for this progression of breast cancer. What I'm talking about is basically if a woman has the mutation of BRCA1, you know that at a certain point in their life, they're predisposed to breast cancer. When it's going to happen is not easy to figure out, especially for BRCA1 which happens -- the cancers happen in really young women, some of them in their twenties. And at that time, a mammo is not very useful because the density of the breast is too similar to the tumor. So that's why they don't recommend mammograms until older women. And what we are trying to devise is a way to detect this cancer really early in the stage when the second copy of BRCA1 is lost, we're trying to de -- -- we should be able to detect it.
CAVANAUGH: How to make it into a blood test, so women who may have this genetic defect can take it, and therefore know really recall early on before they develop breast cancer that this is happening in their bodies right?
PAO: Exactly. Then you can actually go and take the tumor out really early. That's the hope.
CAVANAUGH: Do we -- this may be a question too far, because your answer may have to be too technical, but did your research discover how this gene gets damaged or deformed?
PAO: Well, we -- the work was basically focused on not how it gets damaged but what happens when it gets damaged.
CAVANAUGH: I see, I see. Well, prior to your discovery, how well was BRCA1 understood by the scientific community?
PAO: Well, BRCA1 from the very beginning was a very controversial and confusing gene. When people first found it, it had no features that were recognizable. People normally when they discover a new gene, they look at the DNA sequence and try to figure out, okay, this thing looks a lot bit like this other gene that we already know had, and that gives us a clue how this thing is working. BRCA1 one had virtually nothing that was recognizable. And then what happened is like people just started looking for things by association, kind of thing. Okay, who are its friends, what can it do? But what happened is people found a lot of things, they were very, very diverse, and they seem to be things that are unrelated. Some of them were DNA damage of the DNA, other ones found that it's not repairing properly, other ones found that it affects the growth, etc., etc. But many different functions. And so people just camped it into whatever they liked best and certificated studying it. What this study has done is to bring all these together so we have one theory that can explain all those things at once.
CAVANAUGH: So there were a lot of conjectures about what was going on, but nobody really knew. And one of the things you say in your paper is that everybody -- most of them were a little bit right.
PAO: They were all right because they were all correct observations. People saw things and they were really happening. But people did I understand at which level it was happening. We just had, like something that was basically what we found is if we don't package the DNA correctly then you have problems. You can get all kinds of problems because you can't package it correctly. It's basically if you have a car that doesn't work because it doesn't get gas in the first place, all kinds of things are not going to work in the car.
CAVANAUGH: I'm speaking with doctor Gerald Pao, he's a bis on at the Salk institute. And we're talking about a paper that's going to be published in nature this week, and it's announcing a break through in breast cancer research, most specifically about breast cancer, that is the type that is genetic. And specifically women who have a genetic risk of developing breast cancer might be affected by this research. How exciting is this discovery for you?
PAO: Oh, this was very, very exciting for us, very me, personally. I started my PhD. With doctor Burma, working on this thing. I was working on something else, and then just fortuitously I found something with another doctor, a fellow in the lab when I was a graduate student. I started working on BRCA1 at that point. And we had a hint that it might be doing something along these lines. But we really did not know. We couldn't really prove it. And when we made the key observation was actually, like seven years ago. Chen Zu, the coauthor of this paper, she and I were looking at a microscope, looking at a genetically modified mouse that did not have BRCA1 in the brain, and by looking in the microscope, we had that insight what it might be doing. It was just this Eureka moment that we actually looked at it, and was, like, wow, I think this might be it, you know? We actually had this kind of moment. But it took us seven years to prove to the scientific community from the point that we saw it, it was a lot of hard work and trying to design the proper experiments to actually prove it to everybody else. Because you have extraordinary evidence, and that's what we're going after.
CAVANAUGH: That's the kind of a moment a scientist must remember all his life.
CAVANAUGH: Now, for a woman who has a mother or an aunt or a sister who has developed breast cancer, what are her options now for early screening and treatment?
PAO: Well, there are several types of intervention that people typically have. One is -- well, some of them advocate that if you don't have BRCA1 or BRCA1 two mutation, the most radical of those sessions of the treatments that have been proposed is total mastectomy and hysterectomy. Basically just remove your breasts, remove your ovaries, and remove all the tissue. But the problem is that some people have found the little that's remaining it kill cause cancer. So the benefit of that is not completely clear because it affects the quality of life of people and that's also a problem and that is for women who have been determined to be of the highest risk.
CAVANAUGH: For developing breast or ovarian cancer am were you able to comprehend your findings with how BRCA1 works with actual women who have breast cancer?
PAO: The basic finding that we have in the paper is that certain areas that were considered junk DNA get turned on.
CAVANAUGH: I haven't heard about that before.
PAO: Yes, that's -- so if you actually look thea the entire human genome, about 1.5% of the genome actually contains what we class call genes, things that make proteins, and things we can identify as genes. But the rest of it is what people used to call the dark matter or the junk. And this one was particularly because it's the same sequence repeated over and over, hundreds of thousands of times. People thought oh, this couldn't possibly do anything. People just thought it was junk. What we have uncovered is that if you turn this on, it must be doing something. Because if you turn it on, you can actually cause all this damage in the genome and make the chromosomes break and reassociate inappropriately. And cause a progression of cancer. So it's really doing something, but we have to revisit what we used to call junk.
CAVANAUGH: It sounds to me that what you're saying is the next step in this particular story, this story of BRCA1, may be developing a blood test so that women who have mutated gene may be able to find out they have it very early on. Could we expect this discovery to be used ultimately in a new treatment? A new drug development?
PAO: Well, yes. There are -- also the other thing we found in this paper is that BRCA1 puts a molecular tag on the DNA packaging proteins. And this is a consequence. So certain types of mutations in BRCA1 where people don't have -- they don't put as much of the tag, but they still compensate for it. There's a protein that normal he removes this tag. If we can stop this from removing the tag, we it allow it to accumulate, at least in theory, enough of this tag, that's call ubiquitin, histone H2A, that would relieve the partial loss of BRCA1. You could compensate for it with a drug that would allow -- and we could actually -- we're almost ready to do a screen to look for drugs.
CAVANAUGH: That's fascinating. It took you seven years from that Eureka moment to now to be able to publish the paper. But now wee almost ready to see some new treatment come online.
PAO: Yeah, these treatments, for example, right now in general cancer field, people are reaping the benefits from results of the 1980s. It takes a long time to develop these kind of things. And you actually first have to understand it enough that you can do something about it. And then you have to test it in people, through clinical trial, clinical development, and so on, until people can actually see it in a safe way. You don't want to rush it and make something that's really unsafe because you don't know what the unexpected consequences might be.
CAVANAUGH: Well, you did break this down for us very well, doctor. I appreciate it. And congratulations.
PAO: Thank you.
CAVANAUGH: I've been speaking with doctor Gerald Pao, he is a cancer biologist at the Salk institute.