El cáncer de mama (seno) triple negativo y la proteína TRIM37

Welcome to The Breastcancer.org Podcast, the podcast that brings you the latest information on breast cancer research, treatments, side effects, and survivorship issues through expert interviews, as well as personal stories from people affected by breast cancer. Here's your host, Breastcancer.org Senior Editor, Jamie DePolo. 

Jamie DePolo: Hello, thanks for listening.

It’s been known for a number of years that Black women are twice as likely as white women to be diagnosed with triple-negative breast cancer. If diagnosed with this type of breast cancer, Black women are also more than twice as likely to die from the disease than women of other races and ethnicities. Researchers have been studying a number of factors that may play a role in these disparities.

I’m joined by Dr. Sanchita Bhatnagar, associate professor of medical microbiology and immunology at the University of California-Davis School of Medicine. She also serves as assistant research program leader of the Population Sciences and Health Disparities Program at the UC-Davis Comprehensive Cancer Center. Dr. Bhatnagar’s lab has been studying the TRIM37 gene for more than a decade to understand its role in triple-negative disease. She and her colleagues recently published a paper on their work in the journal EMBO Reports. She joins us to discuss the work.

Dr. Bhatnagar, welcome to the podcast.

Dr. Sanchita Bhatnagar: Thank you very much, Jamie. I really appreciate the invitation to come and talk about our work.

Jamie DePolo: Well, I’m very excited, because this disparity has been talked about, discussed in papers, for quite a while now, and it sounds like you might, you know, be sort of getting to a little part of it. And I know genetics, also, can be a really dense topic, for those of us who are not scientists, to understand. So, I’d like to kind of start at the beginning. Can you tell us how you started to study the TRIM37 gene? Why did you suspect it played a role in breast cancer?

Dr. Sanchita Bhatnagar: Yeah. Thank you for the question. So, I’ll try to begin from the beginning. My journey with TRIM37 started in the lab of the late Dr. Michael Green at the University of Massachusetts Medical School, where I worked on epigenetic silencing. So, when I joined in his lab, he...his lab has previously shown that TRIM37 is required for silencing a tumor suppressor [gene] called Fas.

To give you a background, what tumor suppressor is, we have two types of cancer-related genes. Oncogenes, that is cancer-causing genes, and tumor-suppressor genes that, as the name says, they stop the growth of the tumor. So, they found that TRIM37 is, somehow, silencing what I call the good gene that prevents cancer. How and why was not known. So, I was tasked to understand why it is doing what it is doing and how it is doing that. So, that’s where my journey started.

My work, for the first time, showed that if you have this protein called TRIM37, more than what is needed in a cell, it can cause a normal, healthy cell to become a cancer cell. It was an extensive and a comprehensive study that showed both in the cell models, that is the cells that have been derived from breast cancer patients, as well as a mouse model that we use to study the growth of tumors, and showed that, indeed, TRIM37 is a new breast cancer oncogene. That is a cancer-causing gene.

Jamie DePolo: Okay, let me ask you a question to make sure I understand. TRIM37, the gene...and this always gets confusing to me, because the gene is...the protein and the gene have the same name. It’s just, when you write them out, the gene is italicized, so that’s how you tell the difference. So, the TRIM37 gene, it’s making this gene that stops cancer growth – it’s sort of inhibiting it. It makes it not work, and does that happen with all kinds of cancer? I know you were looking at breast cancer, but do we think it happens for all types of cancer?

Dr. Sanchita Bhatnagar: So, TRIM37 is actually silencing the tumor suppressor, so it's doing the reverse. So, it’s helping to form tumors, right? Yes, I did study it in breast cancer, but there are numerous reports where they have looked into colon cancer, liver, and brain cancer where they do find the role of TRIM37 in causing cancer formation.

Jamie DePolo: Okay, and then let me go into a little more on the difference between the gene and the protein. The gene makes the protein, so is it the protein that’s doing the work, that’s actually silencing the tumor suppressor gene? Is that how it works?

Dr. Sanchita Bhatnagar: That’s exactly how it works. So, what happens is that the question that you may ask is, why do cancer cells have more of this protein? This could be that the gene...the DNA region where this protein is being produced is amplified. So, more than one copy of this gene are present. Or there is just more production of this protein in a cell. And we see that, in cancer patients, that both are true.

Jamie DePolo: Okay, and I want to make sure I understand, too...when I looked at your paper, it sounded like it was a variant of the protein, or was it a variant of the gene that was really driving the growth of triple-negative breast cancer?

Dr. Sanchita Bhatnagar: Right. So, I’ll take a step back and give you a little bit of a background here. The variant that you’re referring to is what we recently showed in our EMBO Reports paper, where we showed that TRIM37 is a signature that associates with racial disparity in triple-negative breast cancer.

So, a very competitive and very smart graduate student in my lab, Rachisan Djiske, she came and asked a question. How does TRIM37 expression look based on races? Are all races expressing the amount...the same amount or not?

And what she found was that the breast tissue extracted from a Black cancer patient, breast cancer patient, expresses much higher level of TRIM37, and not only this...compared to the white women, And not only this, she also found that, if Black women is expressing...the triple-negative breast cancer patient in Black women, if she’s expressing high level of TRIM37, she has poor survival compared to the white women. Another interesting observation she made was that it’s not just limited to cancer tissue. Black women’s breast tissue tends to express much higher level of TRIM37 compared to the white women. The question that came to us, was why is that?

Jamie DePolo: Exactly. That was what I was going to ask.

Dr. Sanchita Bhatnagar: Right? Why would Black women...what is so different that the breast tissue from Black women have higher chances of expressing TRIM37 compared to the white women? We dug deeper, and we looked at the gene level. We looked at the DNA sequence of the gene in Black and the white women. We found single base differences, what are referred to as single nucleotide polymorphism.

Jamie DePolo: SNPs.

Dr. Sanchita Bhatnagar: The SNPs, right, which we refer to as a variant. When we looked at the sequence data that was available through NIH, for Black women and white women, we were surprised to find that this single base pair difference was much more dominant in Black women. Almost 19% of the samples that we looked at had this specific change in gene sequence, which was only 0.15% for white women. And further, we characterized that this single-based change can lead to increase of TRIM37 in the cells. And now, what happens if you have high TRIM37...and that brings in our work that we have done for last 14 years, is that if a cell has high TRIM37, it makes it more susceptible. When and if this cell becomes cancerous, the trajectory would be much more steep compared to the cells that do not have high expression of TRIM37.

Jamie DePolo: Okay, so let me sort of paraphrase here to make sure I’m understanding. I want to go back to the SNPs. Now, my understanding is those are just, like, very small changes. So, those wouldn't, necessarily, say, be classified at the same level as, say, a BRCA1 gene mutation. These are just like...how do I want to say? It’s like somebody took the letters that make up a gene and sort of shook them, and then they’re out of order. So, am I right in that that’s not really considered a mutation, or is it?

Dr. Sanchita Bhatnagar: No, you’re right. It is not considered a mutation, because most of the mutations, you find it in the protein gene. Outside the gene, there is also regions that are important. So, these are called the regulatory region of the gene that decide how much and when this protein should be produced. So, they are called the promotor region. They are called the enhancer region. The particular base difference that we identified, or the SNP that we identified, is present in what we call the enhancer region of the TRIM37 protein. So, it is like putting your foot on the gas, and when you put more pressure, you have more protein.

Jamie DePolo: I see. Okay, and then, for the TRIM37 gene itself, is it in everything, like, every cell, or is it specific to breast cells? Is it everywhere?

Dr. Sanchita Bhatnagar: That’s a good question. Majority of time, it can happen, any tissue of it, but the way we analyze, we only focused on the breast tissue. So, I have only test...my lab has only shown it for the breast tissue, but that doesn't rule it out that it’s not present in any other cells. We tried to just control the population cell type so that we can make a more conclusive decision there.

Jamie DePolo: Okay, and then, so, if I’m understanding correctly, if cells have more of this protein, if they do...if something happens to them and they start to become cancerous, that it’s going to be much worse if they have higher levels of this protein. They’re much more likely to grow faster? Is that right? Perhaps metastasize, spread to areas beyond where they start? Am I understanding that correctly?

Dr. Sanchita Bhatnagar: That’s absolutely correct, Jamie. So, my previous work in the lab showed that TRIM37 is not only forming a tumor, but it is also important driver of metastases and resistance to chemotherapy. And this is very important, because we know that majority of the deaths that we see in cancer patients is from the metastases. It’s not the primary tumor that is fatal. So, even if we know what...if we know a gene that caused the tumor, is not that critical, because the reason of the death in the patient is not because of the tumor causing, but it is the spread of the tumor.

So, when I started my own lab in University of Virginia as an assistant professor, that was a question that I was fascinated with. What if TRIM37 that is capable of forming a tumor by itself, has any role whatsoever in metastases? And we, again, showed, comprehensively, that TRIM37 can drive metastases, as well as help develop resistance to chemotherapy. So, making it, again, a very important protein that, if can be targeted, can be utilized for treatment approaches.

Jamie DePolo: Okay, and when you say targeted...I want to make sure I understand this. The idea would be that somebody would develop a medicine that would lower the levels of this protein or perhaps even silence the gene so the protein isn’t made? Is that the goal?

Dr. Sanchita Bhatnagar: Right. So, TRIM37 is a protein, but it has a job to do. So, it has many functions within the cell that it does...what we call an enzyme. So, many of the drugs that we see, when we say they target a protein, they are preventing this protein or enzyme from doing its job. So, the idea would be that, even if we can’t reduce the amount of protein, we somehow interfere with its function. So, the example that we use in our classroom is lock and key.

Any enzyme is like a lock, and its job is to get the key into it and then open it. If you have a wrong key, it will compete with the likelihood of the right key to open the lock. So, what we think is, if we can find a competitor that goes and binds the lock in a way that the right key cannot open it, we did the same job of not reducing the protein, but stopping it from doing whatever it needed to do. So, the need right now is, because we have extensive data to show that TRIM37 is an important target for developing new treatments, now we want to develop a chemical inhibitor that can stop it from doing its job.

Now, that being said, you can argue, how do we know it would work or not? There is no guarantee, but again, going back to my work from the lab where we showed, actually, that if we can take this protein out of the cell, a cancer cell, we can show, in the mouse model and in cellular model, that is sufficient to stop the spread of cancer cells in the mice. So, we have pre-clinical. We have proof-of-concept data to prove that, if we can find appropriate drug, we can actually develop it, and it, most likely, will be effective.

Jamie DePolo: Okay. I want to make sure I understand the idea, because, to me, it almost sounds like what tamoxifen or an aromatase inhibitor does. It kind of sits in that estrogen receptor and stops estrogen from making the cancer cell grow. So, it sounds like, if you could find this treatment that would sort of sit in the receptor for the TRIM37, you know, it would be that the competing key, then the protein or...couldn't do its job. Am I understanding that right?

Dr. Sanchita Bhatnagar: That’s exactly what it is. The only thing I would say is that TRIM37 is in the cell. So, it’s not sitting on the surface of it. So, that’s the only difference, but the idea would be the same.

Jamie DePolo: Okay. Well, that sounds amazing. I am wondering, do we know why there is more TRIM37 in the triple-negative breast cancers of Black women, or as you said, just in their breast tissue in general? Do we know why that is?

Dr. Sanchita Bhatnagar: There could be many reasons. One of the reasons that we put forward was that genomic variant that we identified in the Black women’s breast tissue. That the women with this particular SNP tend to have higher levels compared to the white women. Now, that being said, it doesn't mean that white women cannot have high TRIM37. There could be other mechanisms, but one of the susceptibility factors that we believe can be used as a predictive biomarker is the women who have much likely or have a family history of developing triple-negative breast cancer can be screened for this SNP, and that can guide the treatment regimen or even just monitoring them much more closely. So, I would not make a claim that it can be something like a BRCA, but it can at least guide it through.

Jamie DePolo: No, that makes sense, because, you know, I know people personally who have been diagnosed with triple-negative disease. They had genetic testing. They don’t have any mutations, but they have this history of breast cancer in their family, and this kind of suggests this could be one possible reason for that. Perhaps they have this SNP that is linked to the...

Dr. Sanchita Bhatnagar: Yeah.

Jamie DePolo: Okay. Okay. So, it sounds like, going forward, there are almost two things that you might be doing, and you can tell me if you’re doing both or either or none, but working on developing this treatment that could sort of neutralize the effect, but then, also, figuring out some sort of biomarker test or you know, something that becomes standard that people could use to screen for this, and is your lab going to work on both of those?

Dr. Sanchita Bhatnagar: Yeah, those are both excellent opportunities, and I wish we could do that, but you know, research requires both personnel and funding. So, you know, we are going to take some baby steps. Right now, I think the first priority is to find out a small molecule inhibitor that can directly inhibit TRIM37, because I think that opens lot of opportunity.

There’s always new targets and new therapeutics needed to help the breast cancer community, and I think this gives us some directions there, and because of our experience with TRIM37, we feel more confident, and you know, we have much more experience in delving that direction, and I also want to utilize our nanoparticle designs that we have generated from our previous work.

Just to give you a little bit background on that, so, nanoparticles are like lipid balls. Now, one of the problems that we see with chemotherapies and other treatments, cancer treatments, is adverse effects, side effects. The reason being, they’re not only killing the cancer cells, but also the surrounding tissues. So, there is a lot of need for focused delivery. So, we have these nanoparticles base, which are lipid-based vesicles, where we can put these drugs, package them in those vesicles, and deliver them with the address on them.

That’s how we call them. We call them smart nanoparticles, because we have an antibody on the surface of these nanoparticles that targets only cancer cells, triple-negative breast cancer cells. So, we really hope that we cannot only just identify the drug, we can also have a whole package, along with the delivery platform, to reduce and minimize the toxicities that are often seen with these treatments.

Jamie DePolo: Okay. So, it’s almost like the lipid particles...I mean, call it what they are. It’s fat. So, it’s like the medicine that’s going to kill the cancer is kind of wrapped in this ball of fat, to be very blunt, and then it’s got a tag on it that is sort of seeking out the cancer cell. So, it passes through the body, and it doesn't unleash the medicine until it gets to the cancer cell. Am I understanding that correctly?

Dr. Sanchita Bhatnagar: Exactly.

Jamie DePolo: Yeah, okay. Okay, well, that sounds amazing. Dr. Bhatnagar, thank you so much for joining us and explaining your research. This is very exciting. I am going to definitely keep an eye out, because I think this would be so fascinating, as you move forward, to see what develops.

Dr. Sanchita Bhatnagar: Thank you very much, Jamie. I really appreciate this opportunity.

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