Steroid hormone intervenes in the endometrial tumorigenesis of pten ablation
Hong Im Kim1, Tae Hoon Kim1, Jeong Mook Lim2
1Department of Obstetrics and Gynecology & Reproductive Biology, Michigan State University College of Human Medicine, Grand Rapids, MI 49503, USA.
Background:
Endometrial cancer, the most common gynecological cancer, is closely associated with endometrial hyperplasia, unopposed estrogen exposure, and genetic alterations. Phosphatase and tensin homologue (PTEN) is a tumor suppressor genes completely lost or mutated in >50% of primary endometrioid endometrial cancers. Estrogen-dependent endometrioid carcinoma is the most common type of endometrial cancer. Progesterone is a hormone that antagonizes the growth-promoting properties of estrogen in the uterus. Progestin is used as a conservative endocrine treatment of early endometrial cancer in order to preserve fertility as well as a palliative measure for advanced-stage patients. Progesterone therapy has been shown to be effective in preventing endometrial cancer as well as controlling growth of the endometrium. However, the effectiveness of progestin for women with endometrial cancer is less clear.
Methods:
In order to understand the effect of steroid hormone on endometrial cancer progression, we used a mouse endometrial cancer model with conditional loss of Pten in the mouse uterus (PR (cre/+) Pten (f/f) , Pten(d/d) ). To assess the effect of steroid hormones, ovariectomized Pten(f/f) and Pten(d/d) mice were treated with estrogen or progesterone over a period of three month.
Results:
Uterine weight gain was significantly decreased in ovariectomized PR (cre/+) Pten(f/f) mice compared to intact PR (cre/+) Pten(f/f) mice. Ovariectomized PR (cre/+) Pten(f/f) mice treated with P4 or vehicle also exhibited decreased uterine cancer size compared with intact PR (cre/+) Pten(f/f) mice. Proliferation of ovariectomized PR (cre/+) Pten(f/f) mice treated with P4 is highly decreased compared to other groups. The levels of stromal progesterone receptor were highly increased in ovariectomized PR (cre/+) Pten(f/f) mice treated with P4 which resulted in decreased epithelial proliferation.
Conclusions:
These results suggest that P4 treatment significantly reduces tumor mass but does not affect cancer progression in PR (cre/+) Pten(f/f) mice.
Insights
Progesterone therapy significantly reduced uterine cancer size and proliferation in a mouse model. However, this treatment did not alter cancer progression, suggesting a complex role in endometrial cancer management.
Area of Science:
- Gynecological Oncology
- Endocrinology
- Cancer Biology
Background:
- Endometrial cancer, the most common gynecologic malignancy, is linked to hormonal imbalances like unopposed estrogen and genetic factors, notably PTEN mutations.
- Progestin therapy is a fertility-sparing treatment for early endometrial cancer and a palliative option for advanced stages, though its efficacy remains debated.
- Phosphatase and tensin homolog (PTEN) is a critical tumor suppressor gene frequently altered in endometrioid endometrial cancers.
Purpose of the Study:
- To investigate the impact of steroid hormones on endometrial cancer progression using a genetically engineered mouse model.
- To evaluate the therapeutic potential of progesterone in reducing tumor burden and affecting cancer cell proliferation.
Main Methods:
- A mouse model with conditional loss of Pten in the uterus (PR (cre/+) Pten (f/f)) was utilized to mimic endometrial cancer.
- Ovariectomized mice with and without Pten loss were treated with estrogen or progesterone for three months to assess hormonal effects.
Main Results:
- Progesterone treatment significantly decreased uterine weight and tumor size in ovariectomized Pten-deficient mice.
- A notable reduction in epithelial cell proliferation was observed in mice treated with progesterone, correlating with increased stromal progesterone receptor levels.
- While tumor mass was reduced, progesterone treatment did not alter the overall cancer progression in the Pten-deficient mouse model.
Conclusions:
- Progesterone therapy demonstrates a significant tumor-reducing effect in this endometrial cancer model.
- The findings suggest that while progesterone can decrease tumor mass, it may not halt or reverse cancer progression in the context of Pten loss.
