What does PR+ cancer mean?
- PR+ means the cancer cells produce progesterone receptor proteins, which are designed to bind to progesterone.
- PR+ status is usually found alongside ER+ (estrogen receptor positive) status in many hormone receptor-positive breast cancers.
- When a tumor is both ER+ and PR+, it typically suggests a more differentiated, less aggressive, and better prognostic type of cancer.
PR+ cancers tend to have a better prognosis.
This is because the presence of progesterone receptors shows that the tissue is still relatively normal. Healthy breast cells naturally express both estrogen and progesterone receptors.
When a tumor remains PR+, it means the cells have not completely lost this normal hormonal identity. They are still influenced by the body’s regulatory signals. This means that they will be more responsive to therapies like tamoxifen or aromatase inhibitors.
In contrast, when a tumor loses PR expression, it suggests that the cells are becoming more disorganized, and less controlled by normal hormonal pathways. This can lead to faster, more aggressive growth.
PR positivity is therefore a sign that the cancer is still partially following normal biological rules, which is associated with a slower progression and better response to treatment.
There’s a common assumption that “If a tumor is PR-positive, giving progesterone will make it grow.”
However, the presence of progesterone receptors doesn’t necessarily mean progesterone promotes cancer growth. It just means the cells respond to progesterone, and in many contexts, that response is actually anti-proliferative, not stimulatory.
There are a few things to know:
- Progesterone receptors increase in response to high estrogen levels.
High estrogen levels stimulate the production of more progesterone receptors (PRs) inside cells.
Estrogen binds to estrogen receptors (ERs) and directly activates the gene responsible for making progesterone receptors, increasing their expression.
So when a tumor is PR-positive, it often reflects a history of high estrogen exposure, not that progesterone itself is causing harm.
Increased PR expression is a protective mechanism. Progesterone counteracts and regulates the proliferative effects of estrogen. In this way, the increase in PR is not harmful, it is the cell’s attempt to keep cell growth more controlled and orderly. Therefore, PR positivity could be seen as a protective feature rather than a risk factor in hormone receptor-positive cancers.
- When estrogen is blocked (with antiestrogens), PR expression drops sharply.
A study published in Endocrinology found that progesterone receptor (PR) production in breast cancer cells is driven by estrogen signaling.
When estrogen (or even low-dose tamoxifen, which acts like estrogen) binds to estrogen receptors, it activates the gene for PR, causing cells to produce more progesterone receptors.
The authors concluded that PR expression depends on active estrogen signaling.
- Hormones can impact cells independent of the receptor.
Progesterone and estrogen can affect cells even without using their classical receptors. They can send signals through the cell surface, interact with proteins inside the cell, or even affect mitochondria.
A cell without classical PR can still respond to progesterone through other routes, and a PR-positive cell can be influenced in ways that aren’t purely based on the receptor’s presence.
The same goes for estrogen. In fact, there is a lot of research suggesting that estrogen drives triple-negative breast cancer (TNBC), even though TNBC tumors lack detectable estrogen receptors. Studies show that even without using its usual receptor, estrogen can trigger pathways like MAPK and PI3K/Akt, which promote cell proliferation.
Just because a tumor expresses progesterone receptors does not mean that progesterone is promoting its growth, any more than estrogen receptor loss prevents estrogen from driving cancer in TNBC. Progesterone’s main role is to stabilize cells, balance estrogen’s growth signals, and promote healthier differentiation. Because hormones act through multiple routes, not just the classical receptor, PR positivity simply means the cell can still respond to progesterone, and in most cases, that response is stabilizing, not dangerous.
- Blocking progesterone does not necessarily stop the growth of PR+ cancers.
Research published in Nature shows that progesterone binding to its receptor can actually alter estrogen receptor (ER) activity, steering it away from genes that promote aggressive growth.
In breast cancer models, adding progesterone slowed tumor proliferation, while blocking progesterone did not improve outcomes. Without progesterone, estrogen-driven proliferation continued unchecked, leading to worse outcomes.
This suggests that progesterone’s presence often acts as a brake, not an accelerator. So, blocking progesterone in PR+ cancers is not a guaranteed strategy for stopping tumor growth, and may, in some cases, remove a natural mechanism that helps restrain it.
- There is no known mechanism by which progesterone promotes uncontrolled cell growth in cancer.
Unlike estrogen, which directly encourages proliferation, progesterone’s main role is to support differentiation and stabilize tissue structure.
This is why focusing only on receptor status can be misleading. Just because a tumor expresses progesterone receptors does not mean progesterone is fueling its growth. What matters is the biological action triggered by the hormone, and in the case of progesterone, that action tends to limit rather than encourage uncontrolled division.
Understanding the true mechanism behind each hormone’s effects helps correct the widespread misconception that PR positivity means progesterone is causing the cancer to grow. In reality, PR positivity often reflects a tumor that remains hormonally organized and more responsive to treatment, not one that is being fed by progesterone.
So while there is a lot of misunderstanding about what it means when breast cancer is PR-positive, it is unlikely that progesterone is feeding cancer’s growth.
And a large part of the confusion around PR status comes from older studies that linked synthetic progestins, not natural progesterone, to an increased risk of breast cancer. Synthetic progestins are chemically different from natural progesterone and can behave unpredictably, sometimes mimicking the effects of estrogen and promoting cell proliferation. Natural progesterone, whether produced by the body or used in bioidentical form, has not been shown to drive uncontrolled tumor growth. In experimental models, the addition of natural progesterone often slows tumor proliferation and redirects estrogen activity toward safer, more stable pathways.
Understanding what PR positivity truly means is important for treatment. It signals that the tumor remains hormonally responsive and better differentiated, which are traits associated with slower growth, better treatment responses, and better long-term outcomes. PR positivity should be recognized as a favorable feature, not a danger.