Chapter 06: The Effect of Estrogen on Cancer
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Description
Dr. Jones talks his role in the Department of Gynecologic Oncology: to bring reproductive endocrinology back into the conversation about cancer. He talks about "turf wars" that prevented him from pursuing some topics. He explains that he began looking at benign diseases (fibroids, endometriosis) to consider how these might be connected to cancer, as they are over-present in women treated at MD Anderson. He next talks about his studies of the early effects of steroid on cancer, focusing in particular on DES (diethylstilbestrol). He talks about creating the first culture of an immature mammary gland cell line with a functioning estrogen receptor (describing the innovative features of this work). Dr. Jones talks about the mechanisms of cell membranes and indicates that, at the time, researchers were not focusing on the mechanisms of normal tissues. He next outlines the treatments that came from his discoveries.
Identifier
JonesLA_02_20140116_C06
Publication Date
1-16-2014
Publisher
The Making Cancer History® Voices Oral History Collection, The University of Texas MD Anderson Cancer Center
City
Houston, Texas
Interview Session
Lovell A. Jones, PhD, Oral History Interview, January 16, 2014
Topics Covered
The Interview Subject's Story - The Researcher; The Researcher; Overview; Definitions, Explanations, Translations; Institutional Politics; Controversy
Transcript
Tacey Ann Rosolowski, PhD:
All right. Okay. So the red light is on, and the counter is advancing. (laughs) And it is about 10:13 on January 16th [2014], and this is our second interview session with Dr. Lovell Jones in the Reading Room of the Historical Resources Center at MD Anderson. So thank you again for participating.
Lovell A. Jones, PhD:
Well, thank you for the invitation. Segment 06 A: The Researcher; The Effect of Estrogen on Cancer Story Codes A: The Researcher; A: Overview; A: Definitions, Explanations, Translations; B: Institutional Politics; B: Controversy;
Tacey Ann Rosolowski, PhD:
And I really enjoyed our conversation last time, and as I mentioned, I was kind of-make a plan about how to proceed today, and I thought we could start or go back to the thread of the story about your research in estrogen and cancer and talk both about your research, but then also about your role as section leader developing this area of research within the Department of Gynecologic Oncology and Reproductive Medicine.
Lovell A. Jones, PhD:
Right. Interesting that when I came, the department had been, I guess, referring its markers. There was a marker with regards to HCG with a type of ovarian cancer that generally occurred in the young, and the way of following it was measuring this particular hormone.
Tacey Ann Rosolowski, PhD:
And I'm sorry, just the for the record, HCG stands-
Lovell A. Jones, PhD:
Human-human chorionic gonadotropin. (laughs)
Tacey Ann Rosolowski, PhD:
Okay. You remember the acronym but not the name. (laughs)
Lovell A. Jones, PhD:
Yeah, well, I haven't taught endocrinology in about a decade, and even though I'm in the field, sometimes it's connecting the neurons in that part of my brain that says, "Oh, this is the answer to that question." So part of the thought in bringing me was to take over that, but given that it was a moneymaker for Laboratory of Medicine here, they fought it very hard, and what I did was end up with at least one of the research positions.
Tacey Ann Rosolowski, PhD:
Actually, I'm confused. So this was the strategy of marking and then-
Lovell A. Jones, PhD:
This was the strategy in terms of one of the justifications that was given to the Department of Gynecology at the time of having me, because, remember, the research was in one component of surgery, and the other components thought they were doing quite well without it.
Tacey Ann Rosolowski, PhD:
Mm-hmm. Okay. So you were to do research on this area or manage the laboratory which actually conducted the markings?
Lovell A. Jones, PhD:
Part of my duties was to manage that component.
Tacey Ann Rosolowski, PhD:
Okay. And that was a revenue generator.
Lovell A. Jones, PhD:
And that was a revenue generator. But that didn't happen, which was good for me because it allowed me to focus all of my time on developing the research aspects.
Tacey Ann Rosolowski, PhD:
And why didn't it happen?
Lovell A. Jones, PhD:
Because it was a money generator, and the money went to Laboratory of Medicine as opposed to Gynecology.
Tacey Ann Rosolowski, PhD:
So you were kind of in the wrong structural place to do it or-
Lovell A. Jones, PhD:
Well, I was, given that the monies-it would be a reduction in the money for Laboratory of Medicine. They were not keen on letting it go-
Tacey Ann Rosolowski, PhD:
Gotcha.
Lovell A. Jones, PhD:
-and made their wishes known. I guess it was in the discussions more of an abstract, but when there was a live body coming and someone who had a background in that area, then I think what they were thinking is, "Well, if he takes over this, then he has also the capabilities of taking over this that has-." You know. Because they were doing steroid receptor measurements, and one of the things that I was an expert in was measuring steroid receptors. So they could see or at least project that there would be other things that I would be involved with.
Tacey Ann Rosolowski, PhD:
Turf wars. (laughs)
Lovell A. Jones, PhD:
Right. And in the end, we did some collaboration together. And in leaving, there was still a small part of the research I was doing with some of the members of Laboratory of Medicine. So it did form a relationship with regards to the researchers and the faculty within Laboratory of Medicine, but the overall administration of Laboratory of Medicine was initially at the beginning very leery of me.
Tacey Ann Rosolowski, PhD:
Interesting. Huh. So what did you-you said that really freed up your time. So what did evolve from that?
Lovell A. Jones, PhD:
Well, it freed up-it had both a positive and negative. The positive is that it did free up my time to focus on developing the research programs specifically targeted towards gynecology, and then also develop my research and continue research that I was doing when I was at UC San Francisco. On the negative side is that the program that I would have inherited, I guess, had a number of research staff with it, or technicians, and so they stayed where they were. But I did end up with a state-supported research technician for a while. On the negative side, too, is that the funds generated could have been refocused and retargeted on things that we wanted to do in the laboratory, but you have to balance the freedom versus the restrictions that came along with it, and I think in the end, it balanced out.
Tacey Ann Rosolowski, PhD:
Mm-hmm. So tell me about these two areas, both developing the research program in gynecology and then how your own research developed.
Lovell A. Jones, PhD:
Well, the research that I was involved with in San Francisco primarily focused on breast cancer, but there are a lot of similarities. I used to joke that of the three specialties in Obstetrics and Gynecology: there is reproductive medicine, there is metabolism, and then there is oncology. The oncologists-I don't know if it's still today, but I would suggest probably pretty close, generally forget all their endocrinology simply because they become pseudo-medical oncologists, kind of a hybrid surgeon medical oncologist, because they are one of the few specialties that also do the surgery but control and are involved in the chemotherapy that goes on with patients, although there is an area of medical gynecological oncology whose group specifically are internists that focus on the chemotherapy. There has always been a kind of unspoken war, because the surgeons kind of tread over into their area, and for a long time that was the kind of sole turf war. For a period of time, there was a truce because the medical oncologists had kind of a joint appointment within the department and kind of worked with the surgeons in terms of the delivery of chemotherapy, but since the two divisions have gotten larger, they've kind of separated. I don't know if that kind of relationship still exists. But coming into the department, I guess my thought was to bring endocrinology, especially reproductive endocrinology, back into the lexicon, and as you can see with the name of the department, or the change of name, over the last decade, they've brought in reproductive medicine components of gynecology. So there are benign diseases that are now under the auspices of Gyn Onc. And I think part of my role in the department was to get them to think about those aspects, because I work with some of the fellows who are looking at benign diseases as related to endocrine disorders such as endometriosis, fibroids, which are benign conditions but can cause major issues.
Tacey Ann Rosolowski, PhD:
What kind of issues? I mean, how are these benign diseases connected to cancer?
Lovell A. Jones, PhD:
Well, you know, their uncontrolled growth, to an extent. The only difference is that they don't metastasize, but they can create major health problems, some life-threatening if the fibroids get too large and end up resulting in heavy bleeding. The same thing with endometriosis in terms of more infertility than life-threatening, but if it gets out of control, it can get to that point as well. And, you know, the women who came here for their surgeries would also suffer from these benign conditions, so do you refer them out or do you treat them in-house, I think was the thought behind a lot of this. So in developing a women's or uterine [unclear], that made for a natural in terms of its inclusion.
Tacey Ann Rosolowski, PhD:
So tell me about how your research developed. I mean, you began the breast-related research in San Francisco. Now, did that continue, evolve?
Lovell A. Jones, PhD:
That continued here and continued with collaborations outside the department.
Tacey Ann Rosolowski, PhD:
Tell me about that.
Lovell A. Jones, PhD:
Those collaborations actually started, as I mentioned before, with the Kelsey-Seybold, because a lot of the research was targeted towards early detection and trying to find markers, especially endocrine markers. We had developed a test, actually, which was funny, because we developed the methodology when I was at UC San Francisco that we published in the Journal of Biological Chemistry to look at the bioavailable level of steroids. There are biologically active components which are free in the circulation, and there are biologically inactive components which are bound to some binding protein within the body, and those that are bound to that protein generally don't have access to the receptor mechanism, the given biological action. So when I was in San Francisco, we looked at and developed ways of determining the percentage that was biologically available and then began to notice that that was a difference between women who developed-who had breast cancer, and those who did not, and then those women who had some risk factors for breast cancer, that there was a difference in those women. And so when I got here, I wanted to pursue that in terms of seeing whether or not it is predictive, that that occurs before the woman develops or has evidence of the disease. So that's why the relationship was started with Kelsey-Seybold.
Tacey Ann Rosolowski, PhD:
Now, you mentioned yesterday that it was via the connection with Kelsey-Seybold that you were able to involve, you said, normal women and-
Lovell A. Jones, PhD:
Right. Disease-free.
Tacey Ann Rosolowski, PhD:
Disease-free. So what was the objection at MD Anderson? Was there an objection at MD Anderson to including disease-free patients or-
Lovell A. Jones, PhD:
Well, I think, first of all, they weren't set to handle them. The second is that I guess there had been a historical divide between MD Anderson and Baylor, and so Kelsey-Seybold was part of Baylor. And being an HMO, being the first in this area, there was kind of an unwritten rule that you stayed within house. So fortunately for me, one of the former fellows, Chris Gilbert [phonetic], who trained here at Anderson, went over to-he and another, not former fellow from here but another oncologist, John Hughes [phonetic], started their Cancer Center over at Kelsey-Seybold but also was involved in seeing normal-disease-free patients. And in Gil's-actually it's Gil [unclear]. Gil's father-in-law was a-I'm trying to remember his father-in-law's name-was a major player here at Anderson, and Gil wanted to start a research program. I had a program that I wanted to do, and so we hooked up. In fact, one of the individuals whose first research papers came out of that is Sally Vernon [phonetic], who's now a full professor over at the School of Public Health. But that paper was looking at the level of bioavailable estrogen as a marker for breast cancer risk, and the only way we were able to do that was with the patients or the individuals that they saw through Kelsey-Seybold.
Tacey Ann Rosolowski, PhD:
So was the discovery that there was a significant ability to use this as a marker?
Lovell A. Jones, PhD:
It never really came to fruition, because, first of all, it was a difficult assay to do, and we could never get corporations to buy into it, although it has been used for other diseases. And unfortunately, we never did patent it. So one day this salesperson came into the lab and he said, "We have this device that we think you'd be interested in that's able to determine free levels of different steroids [unclear]." I said, "Oh, you do?" And he brought the device and showed it to me, and I said, "Hmm, looks interesting." And then something must have clicked, something I said, and he went back and looked at the references on the brochure he'd put together, and he says, "Are you that person?" I said, "Yes, that's me." (laughter) He never came back. He must have thought we were going to sue him or sue something, but we didn't have a patent. So he just made a minor change in the device and then went ahead and patented it. But it's still used today in measuring things. But our intent at the time before biotech firms and that sort of thing came into being was basically to develop a technique that would benefit people, as opposed to generating money. But I think some of the benefits that have come out of that is relationships. I think we may have had a small part in the relationship, because other people piggybacked on our relationship with Baylor and Kelsey-Seybold. I don't know if there are any programs now with Kelsey-Seybold. There are a whole lot of programs now with Baylor in terms of moving forward along those lines. But the other research I continued was to look at early effects of steroids on development in specifically cancer. That research somewhat got me in a little trouble because a number of the major pharmaceutical companies were involved in producing diethylstilbestrol and at the time were on the suit from the women who were at risk for developing cancer and their parents, who felt guilty about taking these compounds and putting their children at risk. And given that I was one of the main players in that research area and in a Gyn Onc department did not blend well, and there were a lot of discussions about my continuing that line simply because-
Tacey Ann Rosolowski, PhD:
Even though you were examining the cancer risk?
Lovell A. Jones, PhD:
Mm-hmm.
Tacey Ann Rosolowski, PhD:
Wow. That's strange.
Lovell A. Jones, PhD:
Well, it was because a lot of the support for the studies done, at least in Gyn and other areas along those lines, were from these same companies.
Tacey Ann Rosolowski, PhD:
Okay, seemed like conflict of interest. Yep. Yep.
Lovell A. Jones, PhD:
Yeah. So they were, like, either-it never happened, but it was brought to a point of discussion, I'd say, of whether I would continue to do what I was doing or they would continue to give money that they were giving. They continued to give the money, and I continued to do what I did, and we kind of had a happy medium going forward.
Tacey Ann Rosolowski, PhD:
So what came out of that research?
Lovell A. Jones, PhD:
Well, they no longer give steroids to pregnant women, at least not that I know of. But as I mentioned before, the issue that's still being debated is now in-vitro fertilization with the hormones that are in that medium that they do in-vitro fertilization in. So there's still work to be done, but that was a major change. Some of the work led to DES registries that now follow-I don't know if they still fund it as well as they were before, but now follow these women through their lifespan to at least bring them in for earlier examinations and monitor them. And some of the work we did was to say that although the initial cancer occurred-in fact, the youngest was seven-
Tacey Ann Rosolowski, PhD:
God.
Lovell A. Jones, PhD:
-occurred in their teens and early twenties, that this was a disease that normally would occur in women past the age of fifty, sixty. And given that the bulk of women now probably are entering that age range, and given that this is a disease more common of them at that age, that they may be at higher risk for developing more of those types of cancers, so they should be monitored even more. That was accepted a number of years ago, but given the financial condition of the country and [unclear], I don't know how well that's still supported. But Houston was the center of that for a while, too, especially in terms of African American women, because of St. Elizabeth Hospital here. Some of the physicians at that hospital gave African American women diethylstilbestrol early in their pregnancy.
Tacey Ann Rosolowski, PhD:
God.
Lovell A. Jones, PhD:
So fortunately, unfortunately, depending on your way of looking at it, it wasn't done in a lot of other parts of the country, so it is not a big issue in terms of African American women. It's primarily white females, primarily on the East Coast, Chicago, very little on the West Coast.
Tacey Ann Rosolowski, PhD:
Has there been more of an effort here in Houston to track these women, both white and African American, who were given DES?
Lovell A. Jones, PhD:
There was a physician over at Baylor, who has since died, who was in charge of the DES registry, and I don't know if anyone has picked it up since he died. In fact, that's the person I did a lot of research with on moving from animals to humans and looking at the potential DNA damage that occurred in these women similar to what occurred in mice, and actually published a number of papers on that.
Tacey Ann Rosolowski, PhD:
Was that a dramatic shift from doing work on animal models to working with human populations? When did that happen in your work?
Lovell A. Jones, PhD:
Probably-well, the free steroid work was always done in humans. The DES estradiol stuff started in animals and transitioned to humans probably in the early nineties when we started this relationship with Kelsey-Seybold. And then I began to develop relationships with other faculty and came across the DES Registry at Baylor and then approached the guy who was heading it about doing some research on the women, specifically those who had not developed cancer, to see if we could pick up any particular abnormalities in these women before the disease occurred.
Tacey Ann Rosolowski, PhD:
Yeah, I was thinking that you had the phrase that you used a number of times yesterday, "from discovery to delivery," and it seems like working with human populations is a quicker route to make that happen-
Lovell A. Jones, PhD:
Right.
Tacey Ann Rosolowski, PhD:
Yeah, than with animal models. Yeah. I had read somewhere in my background that you created the first culture of immature mammary gland, a mammary cell line.
Lovell A. Jones, PhD:
Yeah.
Tacey Ann Rosolowski, PhD:
And I was wondering if you could explain to me more about that and tell me what the significance of that was.
Lovell A. Jones, PhD:
Well, the steroid receptors and the measurement of the steroid receptors have always been done in abnormal tissue. In fact, if you look at normal mammary gland, both humans and animals, it's very hard to detect receptor levels because they have very low numbers. Yet that is the primary role by which steroids are biologically active. So what we wanted to do, the graduate student that I had with me, Donna DePaulo [phonetic], is to look at if the receptors are at such a low level, how are these steroids operating in causing this change? So what we came across in the literature and were able to show in the model system we were using was that steroids actually had two separate mechanisms, one by membrane action. And Claire Zego [phonetic], who was actually almost run out of the field-in fact, she was to some extent, for heresy, because she was the first to propose the idea that steroids actually had a membranal effect, and she was going against the tide of Singer [phonetic], who-I'm trying to think of the other guy, a Frenchman-it'll come to me-who first discovered steroid receptors. And everybody in the field said, "Ah, this is the way that steroids operate," because their mode of action is very slow. A protein or a membrane receptor, the action was very quick. Hit it, boom, instant reaction. For steroids, it takes a while, and primarily because the steroid has to go to the nucleus, the nucleus has to generate proteins, proteins generally generate an effect, and then you see something happen. Whereas in the membrane, the protein mechanism is already there [unclear]. [snaps fingers] Boom, boom, happens. Elwood Jenkins [phonetic]. The model that was created by Elwood fit the pattern, so everybody went that way. And when Claire Zego came along and said, "Oh, no, no, there's-," people said, "Rubbish," blah, whatever. But she was persistent, and there's now a field of thought that there are other mechanisms, that the primary mechanism is through the cytoplasmic receptor, but there are other mechanisms that are generated through the steroid going through the membrane. So our idea was, well, let's see if that mechanism is part of the mechanism that results in this change that leads to precancer state. But in doing so, what we realized what was happening was by exposing the tissue early in life, we were up-regulating the production or stimulating the production of receptors, and then these receptors became very evident in developing the cell lines-or cell line, actually-from the exposed tissue. And that was the first time it had ever been done. And the cells ended up in two groups, one that were precancers and one that became immortal. They weren't cancers. You could inject them into an animal and they didn't end up forming a tumor. But they consistently replicated, and there wasn't a finite period, as in normal cells, to their lifespan.
Tacey Ann Rosolowski, PhD:
So what was the significance of that? I mean, I can't-I'm trying to see, like, what did you learn from that?
Lovell A. Jones, PhD:
Well, first of all, it was to show the possible mechanism that was generated that led to this precancer state, that that may be one of the ways in terms of-because when you measure breast cancer, one of the things that is measured is the level of estrogen and progesterone receptors. It's always been fascinating, to me, is that no one has really gone back to looking at normal tissue and trying to figure out how this all comes about in normal tissue. And I think one of the reasons, because people always assumed that estrogens were just promoters, that they didn't play a role in initiation, and so something else came along to trigger this unregulated growth, some chemical, some factor, some inherent [unclear] factor. Then as a part of that trigger, the estrogen receptors came along with it, and therefore led to the increased sensitivity of the tissue, and this was one of the ways that uncontrolled growth occurred, and also led to a whole methodology and treatment in terms of endocrine ablation or anti-steroidal treatments, Tamoxifen, to block the receptors to block the growth. And that set up the two major types of breast cancer, not histological types, but biological responsive types, and that is, estrogen-receptor-negative and estrogen-receptor-positive. The negative ones you treat with chemotherapy because there's no receptor mechanism to ablate, and that sort of thing, and the other, which is in some way considered less aggressive, you treat with hormonal therapy, Tamoxifen, put people on five to ten years of Tamoxifen therapy to, first, in terms of treatment, then in terms of prevention. But no one really gave a lot of thought to how does this tissue, which is hormonal responsive in its growth normally, go from hormonal responsive to hormonally nonresponsive. And that's what the development of this line offered the opportunity to do.
Tacey Ann Rosolowski, PhD:
I'm surprised for some reason that people don't study normal tissue very much, that-
Lovell A. Jones, PhD:
It's hard to keep them alive.
Tacey Ann Rosolowski, PhD:
I see. Huh.
Lovell A. Jones, PhD:
Because they have a finite growth time.
Tacey Ann Rosolowski, PhD:
Okay, yeah.
Lovell A. Jones, PhD:
So immortal cells, HeLa cells, which were the cells that have been used, Helen (sic) Lacks, you may have heard her story-
Tacey Ann Rosolowski, PhD:
Mm-hmm.
Lovell A. Jones, PhD:
-with her cells, because they were the first cells that were immortal, allowed people to study different mechanisms without a finite, because normal cells have about a twenty division, and at somewhere around twenty divisions they no longer function.
Recommended Citation
Jones, Lovell A. PhD and Rosolowski, Tacey A. PhD, "Chapter 06: The Effect of Estrogen on Cancer" (2014). Interview Chapters. 602.
https://openworks.mdanderson.org/mchv_interviewchapters/602
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