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Understanding and Targeting Triple-Negative Breast Cancer with Dr. Jill Bargonetti

Dr. Bargonetti uses dance and other techniques to explain molecular biology, genomics, and more

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.

Read the transcript below: 

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