Why PR+ is good
Sorry if this article has been posted before (it's from July, 2015). I did a quick search and didn't see it.
This article explains how progesterone receptors may help slow cancer down in women who are also estrogen receptor positive, and actually could be a treatment used with tamoxifen. Very interesting! They used actual progesterone in these experiments, not synthetic progesterone found in birth control or HRT.
"Using the same lab-grown breast cancer cells exposed to oestrogen only, the researchers used cutting-edge technology to pinpoint the sites in the cells' DNA where activated oestrogen receptor attached – hence which genes it was controlling.
But when the scientists then added progesterone to the cells too, it caused a rapid shift in the points where oestrogen receptor attached to DNA. At least 470 genes were controlled differently when both hormones were present compared to just oestrogen alone – the progesterone receptor was, in effect, 'reprogramming' the oestrogen receptor, changing the genes that it influences.
But, most crucial part was the overall effect this on the cancer cells themselves – progesterone seemed to cause the cells to stop growing as quickly.
...the team turned to a special technique developed by scientists in Professor Wayne Tilley's laboratory at the University of Adelaide in Australia. This allowed small samples of tumour tissue to be removed from women with breast cancer and grown in the lab for a short time.
Remarkably, the team saw exactly the same effect – adding progesterone at the same time as oestrogen slowed down the rate tumours grew.
They also saw exactly the same phenomenon in mice transplanted with human breast cancer cells: oestrogen fuelled tumours' growth, but progesterone put the brakes back on.
The final, and most crucial, experiment was to see if their findings had any potential implications for treating breast cancer. Again working with mice transplanted with tumour samples and given oestrogen, the researchers used the standard treatment for hormone-responsive breast cancer – tamoxifen, which slowed down tumour growth.
But when they gave the mice tamoxifen AND progesterone, the tumours grew even more slowly."
Read more at http://scienceblog.cancerresearchuk.org/2015/07/08...
Comments
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I posted this on the another forum about a year ago, but there did not seem to be much interest. Personally, I think this research is quite exciting and has great promise. It also helps to explain why those who are PR+ have a generally better prognosis than those who are PR-. The fact that they used preserved/salvaged BC cells from people with BC, as well as BC lines grown in the lab is also intriguing and may perhaps be another (better) way to study cancers in the future.
http://www.cancernetwork.com/breast-cancer/uncover...
"Using ER-positive, PR-positive cell-line xenografts, as well as primary ER-positive breast tumor cells excised from patients and grown in a lab, Jason S. Carroll, PhD, of the Cancer Research UK Cambridge Institute, and colleagues observed that the receptors for estrogen and progesterone physically interacted within the cell. They also found that the global gene expression profile of these cells was different when the cells were exposed to estrogen alone vs estrogen plus progesterone and, in the presence of both hormones, was linked to better clinical outcomes."
http://www.abc.net.au/science/articles/2015/07/09/...
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But this makes we wonder about highly PR+ cancers... is the PR not doing its job? Or maybe it is doing its job so that we would expect to find a negative correlation between a tumor's PR and its size?
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Can you explain how this shows it is beneficial to be PR positive? Having trouble understanding the study
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I agree Labelle, this is very exciting research. I would love to see them do these kind of experiments to see the effect of the hormones vitamin D and melatonin on estrogen positive BC, too.
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Statistically, it has been shown in many other studies that women who are PR+ positive have a better prognosis than those who are PR-. This study doesn't show that is beneficial to be PR+, that has been known for some time. Why being PR+ is beneficial is what has been something of a mystery and what this study is trying to address.
This study seems to suggest having an active progesterone receptor is advantageous because progesterone actually works to counteract the estrogen that we often say for the sake of simplicity "feeds cancer" in ER positive women. Sometimes people think PR+ means progesterone also feeds the cancer. That does not seem to be true and if it were we would expect those with PR+ BC to have worse outcomes (with 2 sources to "feed" the BC).
Actually, neither estrogen nor progesterone "feed" anything. Estrogen receptor positive means the BC is receptive to the signals of estrogen. Estrogen tells cells to grow and multiply-not what we want with ER+ BC. Progesterone tells/signals these cells to do something too. What that is has been the "mystery" although many people (Dr. Lee, most famously) have previously suggested PR "puts the breaks" on estrogen and signals cells to die, which if true, would explain why it is helpful to be PR+. Others have suggested progesterone plays a more sinister role in BC. This study seems to suggest that progesterone (natural progesterone not artificial progestins) may be helpful in treating ER/PR positive BC, especially if combined with Tamoxifen (the strongest response rate in this lab study), because progesterone does seem to signal BC cells to stop multiplying and die (what we want to happen). Early days and all that, but I do think it is an important study. Knowing exactly what progesterone does in the BC setting is pretty important and it seems highly likely it does something, but pretty much all we've used it for up until now is as a prognostic marker (PR+ equals better outcomes).
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Interesting they would suggest tamoxifen showing the strongest response, yet ILC, even PR+ has less to no benefit in many ILC cases.
Clearly cancer is a big ol mystery, even for scientists studying it for decades.
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Yes, and although classical ILC is highly ER+ and PR+, some studies show worse disease-free survival compared to IDC. I wish researchers would always analyze the types separately as a matter of course.
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Labelle and Fallleaves - Thanks for your posts and for the informative links. It's going to be fascinating to see what emerges from this research. I suspect that even five years from now we'll look back and shake our heads at how little was understood of bc. At least, I hope so!
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Perhaps that is why Aromasin includes a steroid as well as anti estrogen.
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My mom who died of BC originally was highly er and pr positive. But when she had mets, it was discovered that her er had decreased and her pr now stood at -0-. Wonder if its reduction contributed to her mets. Hope this angle is pursued. Thank you for posting.
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This is the first I have heard that supports my suspicions about PR - . I did an informal survey of the complications stemming from er+ pr- cancers, vs er+ pr + cancers, and it seemed to be true, that the pr valence mattered to course and outcomes. The clinicians say PR is not relevant, because its the ER that determines tx. I have deeply wonderedif there is more to it. Thanks to all for commentary on this topic
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For those of you interested in ILC, here is an article that offers some possible explanations for the frequent resistance to tamoxifen in ILC cells, and the different effects of estrogen and progesterone on gene expression in ILC and IDC. It's kind of technical, but seems like it has a lot of good information. I just pulled out a few points, but there is a lot more in there. Kind of hard to summarize (or maybe I'm just tired).
Invasive lobular carcinoma cell lines are characterized by unique estrogen-mediated gene expression patterns and altered tamoxifen response
"The partial agonist effect of tamoxifen in MM134 cells may have important implications for the treatment of ILC patients. As a partial agonist, tumor growth may initially decrease versus pre-treatment. Tamoxifen alone induces cell death versus estrogen, and coupled with decreased growth may initially produce a favorable response. However, the overall growth observed suggests that ILC tumors similar to MM134 will outgrow with tamoxifen.
"One of the most strongly induced ILC-specific genes is WNT4. The mouse homolog Wnt4 is a critical mediator of ductal elongation and side-branching during mammary gland development (44). Though Brisken et al. demonstrated that Wnt4 expression is PR-driven, ILC cells may hijack this pathway by placing it under the control of ER. Consistent with this, an ER binding site near the WNT4 promoter is MM134-specific, and is not observed in IDC cells (33). Taken together, ILC cells may utilize a WNT4-driven developmental pathway to drive E2-induced growth."
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Hi everyone. IMO the reason ILC seem to have worse survival rates is because screening for it is much harder than for ILC. So diagnosis is many times delayed and thus the bc is more advanced. This is why its so important to have the proper screening especially with dense breast tissue. Good luck to all....
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From most of what I read, and I realize it is all a moving target, ILC has a better prognosis than IDC, but treating ILC is more difficult (for example, the tamoxifen issue). Now that "they" realize ILC is really a subset of 4 or more types of cancers, it just doesn't make sense to throw a blanket statement out like that.
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- This study did not mention IDC v ILC, but was all about figuring out the role of progesterone in er/pr +BC. When they added estrogen the BC cells grew and multiplied-no surprise there, we've
- long known estrogen has this effect on hormone receptor positive BC cells. When they added Tamoxifen to the same er/pr+ cells they shrank.Again, No surprise. When they added progesterone the cells also shank and when they added both Tamox and progesterone they saw even more impressive results in BC cells shrinking. Without positive progesterone receptors progesterone would not make a difference. This seems to show progesterone may be helpful, so not having progesterone positive receptors means you don't get whatever benefits progesterone might have in fighting BC. From what I can tell no experimenting was done with any AIs in this study, nor was any distinction made between IDC and ILC.
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Labelle, that is the problem, NO distinction was made, yet there are numerous studies indicating tamoxifen does little (even in ER+) ILC as treatment.
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I agree that this is a problem-that so few studies make the distinction-but the purpose of this study was to look at the role of the progesterone receptor.in a general way in HR positive breast cancers.Once they figure that out then maybe they can figure out its role in IDC v ILC BC. Has to start somewhere.
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I am ILC ignorant. After just reading a bunch of studies, many of which contradicted each other on various points, I now realize that ILC is a totally different animal (or group of animals) than IDC. It seems like the scientific understanding of how it works is far behind what is understood about IDC. I just posted that last article because I realize now hormonal therapy doesn't always work the same way in ILC patients as it does in IDC patients. You think, ILC generally has high expression of ER and PR, so great! But various studies have shown tamoxifen doesn't work well in subsets of ILC patients, but letrozole does. And letrozole works differently in ILC patients than in IDC patients (more effective for luminal B than A in ILC, even less so for luminal B in IDC, and not at all in luminal A IDC). Also, (some)studies have shown that short term prognosis is better for ILC than IDC, but not long term. I learned a lot from Wallycat's comment far above!
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Fall leaves, I'm curious about your statement above regarding the relative lack of efficacy of letrozole in Luminal A/B IDC. I've never run across that and would like to explore it further. Would you mind posting your sources? Thanks!
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PR is itself upregulated by the estrogen receptor, so when PR levels are low or absent, it means the estrogen signaling is less active in the cancer and it has started already to be dependent on other growth pathways, not driven as much by estrogen. Luminal B cancers are less responsive overall to hormonal therapy, and you develop resistance to hormonal therapy earlier than people with Luminal A cancers that have high PR expression. That said, the luminal B folks respond better to immunotherapy and to mTOR inhibitors, so its all a trade-off, just helps to understand what cancer subtype you have. My cancer is PR-negative, but has responded well thus far (1 year out) to ibrance/femara.
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Sorry Hopeful 82014! I was referencing the BIG1-98 trial. Here's the pubmed abstract:
http://www.ncbi.nlm.nih.gov/pubmed/26215945?log...
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well now you all have me curious. Cure-ious and Hopeful you are both PR- and have responded well to femara. Are you luminal A or Luminal B or not know. I believe I am luminal A, but don't know for sure. According to Fallleaves Luminal A doesn't respond to femara? I also would like to know more about this info as my MO wants to switch me to femara somewhere down the road
Nancy
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I find this interesting.
My first biopsy results upon original diagnosis, revealed high ER, VERY high PR (95%) and high Her2.
My second biopsy after 16 rounds of neochemo, plus some extra H/P thrown in at the end, showed high ER, low PR (2%) and high Her2.
My third biopsy, of my brain mets, showed middling ER, low PR and high Her2.
I wonder about all the changes but especially about that dramatic drop in PR from before to after chemo.
I have theories but I'm too tired to type them out at the moment....
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The BIG1-98 trial was a large study comparing the effectiveness of letrozole and tamoxifen for early stage breast cancer in postmenopausal and hormone receptor-positive women. There have been various studies that have come out of the trial over the last 5 years, but the general upshot was that letrozole was better than tamoxifen when measured by disease free survival and time to distant recurrence, and slightly better in terms of overall survival.
The more recent study from that trial, that I posted the abstract for, compared the effectiveness of letrozole and tamoxifen in various sub-populations, and found letrozole to be much more effective for luminal A and B ILC patients, and luminal B IDC patients, but found letrozole to be no different than tamoxifen for luminal A patients.
Nancy 2581, I apologize for giving you the impression that Femara doesn't work for luminal A IDC. It does, it's just not better than tamoxifen.
This is an article that explains everything more clearly:
"Tamoxifen or AI: Breast Cancer Subtypes Narrow Choice"
http://www.medscape.com/viewarticle/851937
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Thanks for clarifying Fallleaves. Actually, I like what you posted above even better. If femara is no better than tamoxifen for Luminal A (need to ask my onc about it, but pretty sure I am) I may as well stay on tamoxifen. I don't really have too many side effects and why fix it if it ain't broken.
Nancy
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Interesting reading but has anyone found any information about PR+ outcomes when the patient is ER- ? I can find very, very little information about the significance of PR+ in the absence of ER.
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Fallleaves - thanks for those clarifications and for the link to the original (very interesting) study.
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Ah, it is debated that ER-negative, PR-positive subtype even exists ( http://jco.ascopubs.org/content/26/2/335.full), or is just insensitive immunohistochemistry that does not pan out under close inspection. There are likely other ways to turn on the PR gene, but ER signaling is the usual cause. Single HR-positive subtypes of cancer tend to be more aggressive, but then will sometimes respond better to other targeted drugs, and may more readily jump to HER2-positive (or triple-negative). Luminal A subtypes are ER-positive, PR-positive, the most common. ER-positive PR-negative, HER2-negative are luminal B, assuming they are higher Ki67. But triple positive are their own subtype, etc..
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Bad_At, it may be that cancer evolves to get rid of progesterone receptors in order to fuel its growth (see http://scienceblog.cancerresearchuk.org/2015/07/08...). Mine was doing a good job of that with the low PR at diagnosis of stage IV out of the gate.
Progesterone therapy may increase those cancer-braking receptors, according to the above link, but needs further study.
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Heidihill, that makes sense. I already know I have some smart cancer cells because I'm brain-only. They knew to seek refuge in the brain so I'm not surprised they figured out to get rid of the PR
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