The study, “Targeting progesterone signaling prevents metastatic ovarian cancer,” was published in PNAS.
High-grade serous carcinoma (HGSC) is the most common, and most deadly, form of ovarian cancer. Although considered an ovarian cancer, most HGSC tumors don’t arise from the ovaries themselves, but rather from the fallopian tubes (which connect the ovaries to the uterus).
Metastasis — when cancer spreads to other parts of the body — is associated with substantially worse clinical outcomes across cancer types, and the mechanisms that drive it are not fully understood.
In the new study, an international team of researchers conducted experiments using DKO mice, an animal model wherein mice are genetically engineered to spontaneously develop highly metastatic HGSC. The researchers found that, in these mice, surgical removal of the ovaries (ovariectomy) did not prevent the development of tumors on the fallopian tubes.
However, DKO mice without ovaries had substantially less metastasis and lived significantly longer than DKO mice with intact ovaries (median survival times of 13.2 and 8.7 months). These findings suggested that ovarian factors affect cancer metastasis.
One of the main functions of the ovaries is the production of ovarian hormones, most notably estrogen and progesterone. The researchers hypothesized that the absence of these hormones in mice without ovaries could explain the results.
To test this idea, the researchers treated ovariectomized DKO mice with estrogen, progesterone, both, or a placebo.
Mice treated with progesterone had substantially increased metastasis, and consistently, their lifespans were significantly shorter than mice given the placebo (median 6.5 vs. 12.2 months). Further experiments showed that three weeks of progesterone treatment was sufficient to induce this metastatic effect.
In contrast, estrogen treatment did not increase metastasis. Treatment with both hormones led to the development of metastatic HGSC — however, there was notably less metastasis than with progesterone alone.
“While requiring further study, these data raise an intriguing possibility that estrogen may suppress HGSC development by opposing or attenuating the effect of progesterone,” the researchers wrote.
“Collectively, these hormone supplement experiments indicate that the ovaries of DKO mice produce progesterone sufficient to induce fallopian tube HGSC possessing metastatic potential,” they added. Further experiments using hormones to alter ovarian function also supported this idea.
Progesterone exerts its biological effects by binding to a cellular receptor protein, called the progesterone receptor (PR). DKO mice genetically engineered to lack PRs had substantially reduced HGSC development and metastasis. Blocking PRs using the medication mifepristone had similar effects. Mifepristone, sold under brand names including Korlym and Mifeprex, is currently used to terminate early pregnancies.
These findings “provide compelling evidence that progesterone-induced HGSC development in DKO mice hinges on PR activation,” the researchers wrote.
They then assessed PR expression in mouse HGSCs and in five human tumors. They found that, whereas PR was abundantly expressed in non-cancerous fallopian tube tissue, it was nearly completely absent from the tumors themselves.
“Presence of PR expression in premalignant tissue and subsequent loss of PR expression in HGSC in our study suggest that progesterone/PR signaling is a critical determinant of HGSC development and its metastatic potential — but is likely not a primary factor for tumor progression,” the researchers wrote. They noted a need for further research to explore the distinct roles hormones play in the initiation or progression of tumors.
“Targeting progesterone signaling with antiprogestins [medications that block progesterone signaling] offers a potentially promising therapy for ovarian cancer prevention,” the investigators concluded.
Notably, progesterone has long been thought to have anti-cancer properties, an idea based largely on studies that showed a link between the use of oral contraceptives (which often contain a form of progesterone) or pregnancy (during which progesterone levels are increased) and reduced cancer risk.
This study’s findings “directly oppose the conventional notion that progesterone protects against ovarian cancer,” the researchers wrote.
They noted that these findings may be of particular relevance for women who are known to be at increased risk of ovarian cancer, such as individuals with BRCA mutations.
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