Abstract 4964: Signaling through the progesterone receptor in the tumor microenvironment regulates hormonal sensitivity in endometrial carcinoma.
Authors: Janzen Deanna M. , Rosales Miguel A. , Paik Daniel Y. , Smith Daniel A. , Cheng Donghui , Witte Owen N. , Iruela-Arispe Luisa , Memarzadeh Sanaz 
Published: August 2014

Progesterone, an agonist for the progesterone receptor (PR), can be an efficacious and well tolerated oral treatment for subsets of women with endometrial cancer. Clinically, progesterone is under-utilized as reliable predictors of response are not available. Although progesterone has been used for decades in treatment of endometrial neoplasia, its mechanism and site of action remain unknown. Our study aims to determine how and through which tumor cell types does progesterone exert its anti-tumor effects.

To address these questions we first established an in vivo endometrial cancer model based on the two most common genetic mutations seen in human endometrial carcinoma: cell autonomous loss of PTEN with or without activation of Kras. Importantly in this model we can genetically manipulate the tumor epithelium and stroma independently. Mouse endometrial tumors generated in this system closely resemble human disease. The progesterone hormone with or with out estrogen was administered to tumor bearing mice. When both hormones were co-administered to mice bearing PTEN null endometrial tumors complete resolution of the cancer was achieved. Abundant expression of PR was detected in the tumor stroma throughout this therapeutic time-course. When progesterone was administered without estrogen, PTEN-null tumors persisted and stromal expression of PR diminished. Conditional stromal-specific deletion of PR in PTEN-null tumors was sufficient to convert these hormone sensitive cancers to a progesterone resistant tumor despite estrogen and progesterone co-administration. These results suggest that stromal expression of PR is necessary for anti-tumor effects of progesterone and dual hormone administration is critical for achieving a therapeutic response. Cell-autonomous activation of K-ras is commonly detected in the context of PTEN loss and this genetic combination in our model resulted in a hormone refractory endometrial cancer. A significant reduction in stromal PR expression was found in the PTEN-null/Kras hormone refractory tumors compared to PTEN-null sensitive cancers. Loss of stromal PR in all cases was coupled with diminished phosphorylation of estrogen receptor α at serine 118.

We demonstrate that anti-tumor effects of progesterone are exerted through stromal PR signaling. The loss of PR expression in the tumor microenvironment confers progesterone resistance; therefore pharmacologic restoration of stromal PR should be investigated as a therapeutic intervention in hormone refractory tumors. Regulation of PR in the tumor stroma may be modulated by estrogen signaling. Defining mechanisms of resistance and sensitivity to hormonal therapy will facilitate individualization and wider application of hormonal therapy in patients suffering from endometrial cancer.

Citation Format: Deanna M. Janzen, Miguel A. Rosales, Daniel Y. Paik, Daniel A. Smith, Donghui Cheng, Owen N. Witte, Luisa Iruela-Arispe, Sanaz Memarzadeh. Signaling through the progesterone receptor in the tumor microenvironment regulates hormonal sensitivity in endometrial carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4964. doi:10.1158/1538-7445.AM2013-4964