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In the Spotlight

Endometrial cancer is the most common gynecologic cancer in the United States, with more than 49 000 new cases diagnosed each year leading to about 8000 annual deaths. Unlike other hormonally regulated carcinomas, which usually respond to the antagonists of steroid receptors, endometrial cancer can be successfully treated through the agonistic actions of the progesterone receptor (PR). Even though progesterone is well tolerated, easily administered, and has minimal side effects, ablative surgery, radiation, and chemotherapy continue to be the leading choices of treatment for endometrial cancer in detriment of the less invasive hormonal therapy. This happens primarily because a subset of patients does not respond well to the hormonal treatment, and those with hormone-sensitive or resistant disease cannot be prospectively identified. Therefore, there is an urge to discover reliable biomarkers that would enable the physicians to predict the responsiveness of a particular patient to the hormonal treatment in order to avoid more invasive and hard to endure approaches when possible. As such, Janzen et al aimed to determine the still poorly understood mechanisms and site of action for progesterone in endometrial cancer in hopes of identifying such biomarkers of hormone sensitivity (Cancer Res., June 2013, ahead of print). Using an in vivo endometrial cancer mouse model driven by clinically relevant genetic changes but dichotomous responses to hormonal therapy, Janzen and colleagues demonstrated that signaling through the stromal PR is necessary and sufficient for progesterone antitumor effects. The authors observed that endometrial cancers resulting from epithelial loss of PTEN (phosphatase and tensin gene homolog knock out (PTENKO)) were hormone sensitive and showed abundant expression of PR in the stroma. When the PR was deleted in the stroma of these tumors, they were no longer hormone sensitive, indicating that paracrine signaling through the stroma plays a major role in the progesterone therapeutic effects. In addition, when activation of V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) was coupled with PTEN loss, it led to an innate progesterone resistance due to methylation of PR in the tumor stroma, which could be overcome by the stromal overexpression of PR Thus, the results presented by Janzen et al indicate that stromal expression of PR in the tumor microenvironment may become a reliable predicative biomarker for hormonal therapy response. In addition, their findings suggest that epigenetic de-repression of stromal PR may be a potential therapeutic target to sensitize hormone refractory endometrial tumors to progesterone therapy.