Understanding and Targeting Triple-Negative Breast Cancer with Dr. Jill Bargonetti
By BCRF | March 2, 2023
By BCRF | March 2, 2023
The complexities of triple-negative breast cancer (TNBC) can sometimes make it hard to understand. It’s an aggressive form of breast cancer that is more likely to spread to other tissues––a process called metastasis. TNBCs currently have few biomarkers that can be used to detect, diagnose, and treat it, too.
Dr. Jill Bargonetti’s research into TNBC, various biomarkers, and more has put her at the forefront of discovering not only how these different variables might interact, but also how we might develop novel strategies to accurately identify and kill these cells.
Dr. Bargonetti is a professor at Hunter College, where she also is chair of the Molecular, Cellular, and Development PhD Program Department of Biological Sciences. A BCRF investigator since 2005, Dr. Bargonetti’s BCRF grant is supported by The Estée Lauder Companies' Brands Award in Memory of Evelyn H. Lauder. Dr. Bargonetti has received prestigious awards, numerous research grants, and served as a member of the National Cancer Policy Board and the NIH Tumor Cell Biology study section.
Chris Riback: Dr. Bargonetti, thank you for joining me. I appreciate your time.
Dr. Jill Bargonetti: Thank you for having me.
Chris Riback: When I started to research you and your work for this conversation, I'm sure you already know my reaction. I was like, "Oh man, here we go again. Yet another world-class molecular biologist who also is a one-time dance major and current day choreographer." It doesn't seem these days that you just hear about that combination all the time.
Dr. Jill Bargonetti: Very funny. I enjoy what I do. I get to do a few different things being a professor here at the City University of New York at Hunter College.
Chris Riback: You do, and I have seen it. I've watched and enjoyed some of the video on YouTube, but if you could explain it. We will get into your research, but obviously, the choreographing biologist was something unique in my experience. What is Choreographing Genomics?
Dr. Jill Bargonetti: Choreographing Genomics is a course that I developed where I teach the biology of cancer through postmodern dance. This understanding of the fact that cancer is caused by mutations of particular genes and different genetic pathways and relate the genomics of cancer development to the basic biology of the genomics of every cell, but how it can go wrong and how, when it goes wrong, cells can proliferate out of control. And that is basically what I take the students through from the beginning of the semester until the end of the semester, starting with an understanding of the central dogma, which is that from DNA comes RNA, and from RNA come proteins. And how these different protein products, when mutated, often result in tumorigenesis, we do it through movement.
Chris Riback: It was fantastic to come across, really interesting to watch, and got to the heart, a little bit for me, I felt like one of the reasons why we do these conversations is that communicating these ideas can be done in so many different ways, and to see it done through dance was really creative and really powerful. And I'm sure that your students get a great deal from that.
Dr. Jill Bargonetti: Thank you. I'd like to add that I would love to take it further. Before COVID, we had started a process which we called Touched by Cancer, where we invited people who had been touched by cancer, either as people who had survived cancer, family members of people who had cancer, to understand better what all of a cancer diagnosis means, what the understanding and the meaning of all these genes are. And we would have people who had been touched by cancer join us in the classroom for a few different meetings so we could get their perspectives on cancer and how it touched their lives, their perspective of their understanding. Because they are often undergoing all these different tests, getting to learn about their different sorts of treatment, their targeted treatments, and their understanding of what it means to them, but also perhaps their understanding of what might be going on that can bring a different perspective to the researcher, the student, a student's decision to take on a particular life choice in a career. So it was very interesting to have them with us in the classroom.
Chris Riback: Another great example how connecting happens through all different kinds of sources and avenues and hearing directly from people who have been touched by cancer would surely be a most powerful way, especially for students, who I would assume are just getting into the field.
Dr. Jill Bargonetti: Exactly.
Chris Riback: The conversation, I've now hit the absolute peak of my ability to talk about in a quasi-smart way about dance. That wasn't even quasi-smart how I've been talking, but I've reached my peak there. I'm way out of my field. So let's talk about your research, and this part of the conversation obviously, like dance could, has the potential to get technical, so help me to keep it simple and help explain some of what I'm going to ask you about. Let's start at what I believe is the top.
You are in the middle of extraordinary studies to offer novel therapies to attack triple-negative breast cancer. And to do this, you are studying three critical biomarkers, mtp53, MDMX, and MDM2, and we can get into those individually to the extent that it's useful. And those three critical biomarkers, as I understand it, are known to drive triple-negative breast cancer and other types of breast cancer, and you're looking to determine their role in this adaptation. First, so far, so good, is my characterization...
Dr. Jill Bargonetti: Perfect.
Chris Riback: Okay, terrific. Thank you. I will try to get at least a passing grade in your class. Given that, help me level set. Why is triple-negative breast cancer such a challenging cancer type? Secondly, what are biomarkers, and why are you so interested in them?
Dr. Jill Bargonetti: Okay. Let's start with, first, why is triple-negative breast cancer so hard to treat, and what is it? By just listening to its name, the beginning of its name, triple-negative, it's been classified as something that it isn't, which is a very hard way to classify something, "Oh, you're not this." Or, "You're not wrong, you're triple-negative." So what is triple negative? It means that the cell doesn't have particular types of what are called receptors, and those are things that have targetable therapies. By not having one of those [main] three, it's missing treatments that could target those three things. That's basically it in a nutshell. Because it doesn't have those three targetable things, it's hard to target. What can we identify that it does have rather than saying, "It's not this, what is it?"
Chris Riback: Yes.
Dr. Jill Bargonetti: When we talk about identifying biomarkers, "Okay, it's not those, so let's find some things that it is." If we can identify those biomarkers for something that it is, then maybe we can target something at those. One of the biomarkers which you talked about in the beginning was, you said, mtp53, which stands for mutant p53. And in triple-negative breast cancer, about 80 percent of the time, they have mutant p53. And mutant p53 is a very stable protein in cancers. And in breast cancers that have mutant p53, they have lots of this protein that potentially we could target.
In the past, people have felt that they couldn't target wild-type. Wild-type meaning normal p53. It's been the nemesis of the biotechnology industry for a long time. They wanted to target it, they haven't been able to target it. They have decided to call it non-druggable and forgot about it. But I think that the mutant p53 is potentially targetable, and certainly knowing that cells have a lot of it gives you an avenue to go down because having a lot of it appears to change the DNA metabolism of the cancer cell. That's one targetable now biomarker, mutant p53.
Chris Riback: Yep.
Dr. Jill Bargonetti: Then MDM2 and MDMX are proteins that also interact with mutant p53, so they form a complex. If we use the dance idiom, you could think of it about three people holding hands together. Now you've got a circle as opposed to each one of them dancing off on their own, jumping into the sunset, they're somehow coming together and running in the field holding hands. So, that's what these three things can be together and then drive potentially differences in DNA metabolism for this cancer cell as these three biomarkers.
Chris Riback: Is part of the question how those three dance together? Is it a question of whether the three, in fact, are dancing together or whether any of them are acting alone? How does that connect?
Dr. Jill Bargonetti: Okay. It's good. We have the dance idiom to talk about these things and we use a lot of the same language in dance that we do in science. While they interact together, they also often grab other partners. They might do some things together and they might, at times, leave the group and be asked to go move to a corner and do something different in a corner with another partner, but then be told in the choreography to go back to the center. That may change dependent upon where they are in the piece, if they're at the beginning, if they're in the middle or they're at the end.
And cells, in their process of going from one cell to two cells in this division, they go through many different points in their choreography. So those partners may move around, be together for a while, find other partners, and then they may bring those other partners into the fray. If you didn't have those biomarkers, those other partners may not come in, and some of those other partners may be evil. We might give them an evil personality, in which through that evil personality, they make the division happen more often. Sometimes they might be good, but somehow there's been like a Dr. Jekyll and Mr. Hyde, their personality really changes for the worst, and they start to bring in more evil partners to the mix.
Chris Riback: Which type of partner, and is it a partner, is the PARP1 protein? What are PARP inhibitors, and how do those biomarkers connect?
Dr. Jill Bargonetti: I have a lot of different biomarkers and a lot of different partners that I do look at, and PARP is a protein that is very intimately involved in DNA metabolism. This would be the lover for DNA, just loves it to pieces and helps it stay around. But in cancers, very often, that PARP is working in a way that keeps the DNA there and together, when you would wish that the DNA would fall apart in a cancer cell.
Chris Riback: That confused me because I was reading about that. So it repairs broken DNA. As a layperson, I read, "Oh, broken DNA, that's bad. I would want it to be repaired."
Dr. Jill Bargonetti: Right.
Chris Riback: Talk me through that part of it, please.
Dr. Jill Bargonetti: In a normal setting, as I talked about, you've got this Dr. Jekyll and Mr. Hyde setting. In a normal setting, you would want the DNA repaired, you want that lover there taking care of everything. But in a cell that has undergone a terrible mutation that's going to cause cancer, you want that cell to recognize, "Wow, there's been a problem." For example, when somebody gets a sunburn, "There's been a problem, let's slough those cells off. Let's let those cells die and bring better cells to the top. Let them die. We don't want them anymore, they've got all this damage." Because that's what happens with the sunburn, you get all this damaged DNA. "Let's get rid of those cells."
But what happens is, the PARP, in this setting, is allowing those cells to stay alive. So the PARP inhibitors, for example, have been used in the setting where people have a BRCA mutation, and they're very useful at blocking that PARP from now repairing the DNA, being the lover there in a scenario where the lover should really go away. Maybe there's a twist and there's a pop.
Chris Riback: It's a bad relationship.
Dr. Jill Bargonetti: A bad, bad. So, it inhibits it. And when it inhibits it, the cells die. That's a great thing, because you didn't want those cells because they had this mutation. But in the normal setting, yes, you do want it, but in the cancer setting, you don't.
Chris Riback: Thank you. That makes sense. If we have now covered or at least introduced the various partners, lovers, dancers, and evildoers, and you've established some of the complexity of triple-negative breast cancer, biomarkers, and PARP inhibitors, tell me about your study. What are you looking at, and what are you looking for?
Dr. Jill Bargonetti: When scientists do their work, they come at it based on questions. And they have questions and hypotheses that they derive from small pieces of data that they get little by little. PARP came to us through a screen where we were not looking for it, we just were asking what did mutant p53, this one, partner in the dance, bring to the DNA? What was it doing when there was lots of it? And what we found was, it was helping to bring this partner, this lover, PARP. And it was like, "Why is it bringing PARP?" And the thing that we didn't know about PARP was that PARP inhibitors were being used for cancers that had BRCA mutations but not being considered for cancers that had mutant p53, these mutations in p53, and in triple-negative breast cancer, that's 80 percent of those cancers.
If that PARP inhibitor could be useful in a mutant p53 scenario, we would really bring a treatment paradigm to a large cohort of patients that currently don't have a targeted treatment. Could we address and ask the question if PARP inhibitor-type therapeutic regimes would be useful in settings where you have a lot of mutant p53? A lot of our studies focus in on that question, can these PARP inhibitor therapeutics work to kill the cells that have mutant p53 while not really killing those cells that have the normal wild-type p53? So the Breast Cancer Research Foundation, really, all of the funding they've given us got us focused on this question. And that question is being developed in a number of ways, not just considering the mutant p53 but now considering these other players in the dance, the MDM2 and the MDMX, and how they all might be interrelated in bringing these DNA metabolism-type proteins to allow cancer cells to survive when we would be better off having them dead.
Chris Riback: There are so many permutations, it would seem impossible paths given these different players. What does it mean to define a novel gain of function mutant p53 pathway? In reading about that, why is that so exciting?
Dr. Jill Bargonetti: For us, it's exciting in the fact that so many cancers do have mutant p53. And as I said, in triple-negative breast cancer, it's 80 percent of that.
Chris Riback: 80 percent.
Dr. Jill Bargonetti: Wild-type p53 is a guardian of the genome. Wild-type p53 helps repair and keep that DNA in play. And when the DNA is damaged, it causes the cells to die. But it was thought for a long time that mutant p53 just lost that function. Now, there wasn't this player to make the cells die, but it wasn't doing anything else. Then it began to be clear that some of the mutant p53 that's stable at present and high level has the ability to do other things, but it was unclear what those other things were. Now, the language gets a little bit more complicated, many people have studied what that gain of function is at the level of making the DNA become RNA. That step from taking DNA to become an expressed gene, and that RNA that becomes a protein.
But not many people have examined the gain of function for what the mutant p53 does to the DNA metabolism itself, what it does to those lovers of just DNA, not trying to make it into RNA, but just keeping the DNA successfully there in the cell, not to get sheared and fall apart, which would then allow the cancer cell to continue to exist, perhaps with an even more damaged genome, but a genome that can continue to be inherited in these cells that start to take over the body and become metastatic.
For us, finding that new gained function that was involved in DNA metabolism, it was a very exciting thing because it really hadn't been evaluated before. Now, it's been a number of years ago that our Breast Cancer Research Foundation funding allowed us to identify that pathway through an unbiased screen.
We weren't looking for PARP. It had been something that people generally just used as a marker for cells dying. And here we were deciding, "Oh no, wait. We're not looking at it for cells dying, we're looking at it for cells living." We're now using this as a marker for cells that can continue to exist as opposed to, in the past, it had been used for when the PARP would get cleaved and cut up, it was used as a marker for cells dying. So we're looking at a very different paradigm. We're looking at mutant p53 allowing cells to stay alive, and PARP, allowing cells to stay alive.
Chris Riback: It really comes across in reading about the research, and I know I asked the question why it was so exciting, but in reading about it, it felt very exciting. It really came across that that was something different and something extraordinary. And as you said, looking at it with a different paradigm, what does your work mean in terms of various combinations of chemotherapy drugs?
Dr. Jill Bargonetti: PARP therapeutics are used in patients who have BRCA1 mutations. They are clinically used, but they are not clinically used for patients who have mutant p53. It's not a diagnostic, "Wow, you have mutant p53, let's see what combination therapy we can use to kill your cancer."
Within that, I think that it has a lot of potential applications, and certainly we see that it has efficacy in our cell culture dish and that it has efficacy in our model. But unfortunately, we are not the ones who would be the people who would bring this to a clinical forefront. And how we get that information out there through the Breast Cancer Research Foundation is potentially a way that other people can then take these findings and use these findings in different ways.
And it was in those meetings of bringing us all together that I got to meet Funmi Olopade. And now we are collaborating on this mutant p53, PARP axis, in triple-negative breast cancer, but also trying to determine if we really see it more aggressively in women of African descent because they tend to, or we, people of African descent, get triple-negative breast cancer more often. So looking to see, is this a way that we can really target this breast cancer but would help everybody who gets triple-negative breast cancer.
But it brought us together, and we have a collaborative grant now through the National Institutes of Health, which would never have happened if it weren't for the Breast Cancer Research Foundation funding starting the PARP work, getting me to meet Funmi Olopade, all these amazing breast cancer researchers that I get to meet every year. It's just phenomenal.
Cancer studies and cancer research is basically a lot of different people adding to different pieces of the puzzle, so my little forefront of the world, my research, my lab is a small portion of what happens. There are other people who, hopefully, will find the research interesting and then investigate it in other ways and in other platforms.
Chris Riback: Understood. Maybe that's why my questioning went in that direction because it feels like you're doing something that then has the potential to affect those other areas. And yes, I'm sure plenty of researchers and scientists are looking for ways to take your work and perhaps start their own dance.
What does it feel like to make these kinds of discoveries? I ask because I imagine you must feel a wide range. On the one hand, a scientist and the wonder of discovery, almost like an explorer, is how I was feeling in reading about some of the work. And at the same time, pride and hope for what might be possible for people who have triple-negative breast cancer. What does it feel like to make these kinds of discoveries?
Dr. Jill Bargonetti: I like that you put everything with a positive spin, but sometimes making the discoveries doesn't always have all that positive spin. Sometimes there's frustration in the discoveries. I absolutely believe in this idea of using mutant p53, PARP, MDM2, and MDMX as biomarkers, but how does one get this translated to a clinical setting and utilizing these type of biomarkers and the ideas of the treatment in a clinical setting?
So sometimes it's frustrating because I make these discoveries, I'm thinking things in my head. Sometimes it's very complicated what I'm thinking, and I have these next steps and these next questions. But when I think about people who are struggling with the disease and how one gets these ideas into a clinical manifestation of using these biomarkers and people understanding having p53 roll off their tongue the way BRCA rolls off people's tongue, I find it frustrating that mutant p53 is not something that's discussed in that same way.
But meanwhile, you will say it to people who understand cancer, and they're like, "Oh yes, that's the most important cancer gene, but it's undruggable or it's untargetable." Or "Yes. They all have mutant p53." So it's almost as if sometimes this pathway gets belittled because everybody's like, "Yes. We know they have mutant p53." or "Lots of stuff has mutant p53." But it's so important. It gets frustrating that more people aren't trying to figure out a way to kill cancers that have mutant p53. So I get a little frustrated sometimes.
Chris Riback: Interesting.
Dr. Jill Bargonetti: Making the discoveries is nice, but I've been working on the p53 pathway, as you said, you looked at my research area, and I started working on wild-type p53 in 1990, which is frightening to say out loud. It's a really long time that I've been working in this one gene pathway, although I wasn't looking at gain-of-function mutant p53 at that time. I have devoted my entire professional career outside of getting my PhD to this p53 gene.
Chris Riback: Yes, you have. And yes, I can imagine that there surely must be frustration, and I'm sure on some level that, at some point, acts is fuel. I guess, it must, to keep one going, but yes, it could. It probably acts in both ways, but in the end, I'm sure it must act as the fuel because you're the engine that keeps on going. So where are you going to next? Where does this research go next?
Dr. Jill Bargonetti: We continue to examine the players in the dance, and we keep finding new partners that come in and protect, perhaps, some partners that are more easily targetable. So we have found some that appear to play in the game with the MDM2 and the MDMX that are on the surface of the cell. And it is thought that partners that are on the surface of the cell are much easier to find than if you have to go into the middle. It's much harder to go through this whole group of players. If they're right on the outside, they're much easier to grab.
Some of the studies are moving us to those players that are on the outside, where there are drugs that can potentially target those players on the outside. We're thinking about those a lot. And perhaps by targeting those players on the outside, it can easily facilitate the destruction of some of these metabolic processes that are allowing the DNA to continue to exist when we would wish it wouldn't.
Chris Riback: Dr. Bargonetti, you've been a BCRF investigator since 2005, and your BCRF grant is currently supported by The Estée Lauder Companies' Brands Award in Memory of Evelyn H. Lauder. You've talked about it a little bit, but how would you describe the role that BCRF and Estée Lauder have played in your research?
Dr. Jill Bargonetti: Our research would not be where it is today if it weren't for the Breast Cancer Research Foundation and The Estée Lauder [Breast Cancer Campaign]. They have really allowed us to do the kind of studies that are unbiased, to find this PARP pathway, which we never would've found if it weren't for the funding. And to ask the questions in a way that allows the portfolio to continue to increase in its breath. As I talked about, we're now thinking about things that are on the surface of the cell trying to expand. It gets a little frustrating thinking about this p53 engine that's hard to target.
The Breast Cancer Research Foundation brings people together to think about all these various platforms at the same time. Every year, we get together and we're talking about our research. It continues to allow me to think new ways. And The Estée Lauder Companies has been there every step of the way, including Evelyn Lauder, who really was there with me from the beginning and just supported, as she would call us, her researchers, her doctors, in our quest and in our creative questions. And had faith that our questions would help to eradicate breast cancer, and let's hope that they do.
Chris Riback: Yes, let's hope that they do. And yes, I think we're all grateful that the Estée Lauders, the BCRFs, and the Cooney's won out over the Alvin Ailey's or whatever other company or companies surely would've wanted your talents there. I appreciated the dance metaphor. I think that, in particular, listening to you, it comes across why you would use that as an avenue to communicate. Not the only avenue, your work speaks for itself very loudly and very proudly. Thank you. Thank you for your time. Thank you for the work that you do.
Dr. Jill Bargonetti: Thank you for all of your very pointed questions. And thank you so much for allowing me to bring the dance idiom into my explanation of what I do. I really think that way. I think spatially and I think in movement perspectives, because cells are moving all the time and everything inside the cell is moving, so it really helps to explain the way I think about the biology.
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