Progesterone receptor–positive (PR+) breast cancer refers to tumors that express receptors for progesterone. These receptors act like molecular switches. When the hormone binds, it can influence the cell’s behavior, including metabolism, growth, and gene expression.
PR+ tumors are almost always also estrogen receptor–positive (ER+), because estrogen signaling triggers the production of progesterone receptors. Together, ER and PR status help define a broader group called hormone receptor–positive (HR+) breast cancers, which account for about 75% of all breast cancer cases.
Historically, it has been assumed that because estrogen receptors (ER) promote tumor growth, progesterone receptors (PR) must do the same. But this is a misconception. PR is actually regulated by estrogen, meaning its presence often reflects an active estrogen signaling, not that progesterone itself is driving growth.
The role of progesterone itself has remained poorly understood, and this confusion has led to longstanding caution around its use in PR+ cancers.
Although progesterone receptor–positive (PR+) tumors express receptors for progesterone, clinical treatment strategies have historically focused on blocking estrogen, not progesterone.
- There are no widely used drugs specifically designed to block progesterone in breast cancer. Antiprogestins like mifepristone exist, but they haven’t been routinely used or tested in large-scale trials for breast cancer the way anti-estrogens have.
- Estrogen, not progesterone, has been repeatedly and conclusively shown to drive tumor growth in hormone receptor–positive breast cancers. Estrogen directly stimulates cell division in breast tissue, and decades of research, from molecular studies to large-scale clinical trials, proved that blocking estrogen with therapies like tamoxifen or aromatase inhibitors reduces recurrence and improves survival.
- In contrast, progesterone’s role is speculative. The assumption that progesterone might also fuel cancer growth arose largely because PR+ tumors express the receptor, not because there was strong evidence showing that progesterone itself promotes malignancy. In fact, there is no evidence that natural progesterone independently causes tumor growth
The medical approach has been to simply avoid giving progesterone, not to target or block it.
However, we know mechanistically that progesterone has several anticancer effects. Progesterone:
- Induces cellular differentiation. It encourages cancer cells to mature into more specialized, less aggressive forms.
- Inhibits cell proliferation. Progesterone slows down the rate at which cancer cells divide, partly by suppressing growth-promoting genes like cyclin D1 and MYC.
- Reprograms estrogen receptor activity. It alters how estrogen receptors bind to DNA, reducing estrogen’s tumor-promoting signals in ER+/PR+ cancers.
- Promotes apoptosis. It triggers programmed cell death by upregulating p53 and downregulating survival genes like BCL-2.
- Improves mitochondrial function. It supports cellular energy production and reduces oxidative stress by enhancing mitochondrial efficiency and promoting a shift away from glycolysis toward oxidative phosphorylation.
- Reduces inflammatory signaling. It suppresses inflammatory mediators like IL-6, COX-2, and TNF-α, which contribute to tumor growth and immune evasion
- Stabilizes the tumor microenvironment. It helps maintain tissue integrity and reduce oxidative stress, creating a less favorable environment for cancer growth.
There is no known mechanism by which progesterone promotes 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 promoting 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.Because of its protective effects, progesterone may actually be beneficial for PR+ cancers.
A 2015 study published in Nature provided compelling evidence that progesterone may be used therapeutically in progesterone receptor–positive (PR+) breast cancers. Researchers demonstrated that activating the progesterone receptor (PR) with natural progesterone could actually reprogram estrogen receptor (ER) activity in ER+/PR+ breast tumors, making them less aggressive and more responsive to treatment. Using natural progesterone on PR+ positive tumors reduced cell proliferation and promoted differentiation, effectively softening the tumor’s behavior.
These effects were even more pronounced when progesterone was combined with conventional anti-estrogen therapies like tamoxifen or aromatase inhibitors. This combination produced a greater anti-tumor effect than either treatment alone.
In another study published in the Annals of Clinical & Laboratory Science, researchers conducted in vitro experiments using human breast cancer cell lines to investigate the direct effects of natural progesterone on tumor behavior. They specifically focused on T47-D cells, which express the progesterone receptor (PR), and compared them to PR-negative cancer cells.
Interestingly, they found that natural progesterone significantly inhibited cell proliferation, by up to 90%, and triggered apoptosis (programmed cell death) in the PR-positive cells. Authors concluded that natural progesterone not only slows cancer cell growth but actively helps eliminate malignant cells.
In a 2017 study published in Cellular Oncology, researchers investigated the effects of natural progesterone on breast cancer cell behavior. They conducted in vitro experiments using both progesterone receptor-positive (PR+) and PR-negative (PR−) human breast cancer cell lines.
The study found that progesterone treatment led to a significant reduction in cell invasion and migration in both PR+ and PR− breast cancer cells. This inhibitory effect was associated with reduced the activity of certain proteins (like FAK and cofilin) that normally help cancer cells move and invade nearby tissue. The findings suggest that natural progesterone can suppress the invasive behavior of breast cancer cells through mechanisms independent of progesterone receptor expression.
It’s important to note that synthetic progestins (like medroxyprogesterone acetate) are fundamentally different from natural progesterone. While they bind to the progesterone receptor, which is how they get their name, they do not mimic the biological actions of natural progesterone and can produce very different, sometimes opposing, effects.
Much of the confusion around progesterone in cancer comes from studies that used synthetic versions. Progestins have very different biological effects and are the ones historically associated with increased breast cancer risk in large studies.
Despite promising evidence from lab studies and small clinical trials, there are no large-scale studies investigating the use of natural progesterone in treating progesterone receptor–positive (PR+) breast cancers.
One major reason is that natural progesterone is not patentable, which means pharmaceutical companies have little financial incentive to fund the kind of expansive, expensive trials required to shift medical guidelines. Instead, most of the research, and the guidelines that follow, are based on synthetic progestins, which behave very differently in the body.
Natural progesterone promotes cell differentiation, opposes estrogen-driven proliferation, and may help prevent the invasive spread of cancer cells. It interacts with the progesterone receptor in ways that restore hormonal balance, rather than disrupting it.
As we continue to learn more about how hormones influence cancer behavior, it becomes increasingly clear that lumping natural progesterone together with synthetic progestins is a scientific and medical misstep.
“Physicians should have no hesitation prescribing natural progesterone” (Lieberman and Curtis, 2017).