The Hippo signaling pathway is a highly conserved potent regulator of cell growth, division, and apoptosis. YAP, the nuclear effector of the Hippo pathway, is a highly conserved component of this pathway in mammalian systems. In humans, amplification of the chromosome region containing the YAP gene (11q22) has been reported in several tumor types. This study was performed to determine if YAP expression was present in four common types of malignant tumors which have the highest lifetime risk of causing cancer death among men and women in the United States. YAP expression intensity and distribution were evaluated in normal tissues and compared to the most frequently occurring malignant tumors in these tissues (colonic adenocarcinoma, lung adenocarcinoma, ovarian serous cystadenocarcinoma, and ductal carcinoma of the breast). For each tissue, the nuclear and cytoplasmic YAP expression intensity was scored as negative, low, or high. We found focal expression of YAP in the progenitor and reparative cellular compartments of normal tissue. In contrast, there was strong and diffuse nuclear and cytoplasmic YAP expression in colonic adenocarcinoma, lung adenocarcinoma, and ovarian serous cystadenocarcinoma. We concluded that the potent Hippo growth regulatory pathway shows markedly different expression patterns in normal tissues of the colon, lung, and ovary compared to the three common malignant tumor types we examined in these tissues. Our findings suggest that activation of the Hippo signaling pathway may occur through YAP as part of cell proliferation in normal tissue homeostasis and also might be a frequently activated oncogenic pathway in three common malignant tumor types.

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Objective: Progestin therapy is a fertility-sparing treatment option for women with complex atypical hyperplasia (CAH) or low grade endometrial adenocarcinoma (Grade 1 EA). However, no biological markers have yet been identified that reliably predict response to treatment. Expression of progesterone receptor and activation of the PI3K/Akt/mTOR pathway have been hypothesized to impact the effectiveness of progestin treatment. We investigated whether the expression of progesterone receptor isoforms PR-A and PR-B, and of pAkt and p4EBP1 as indicators of PI3K/Akt/mTOR pathway signaling in pretreatment biopsy specimens predict the response of patients with CAH and Grade 1 EA to progestin treatment. Methods: Premenopausal women with CAH or Grade 1 EA who underwent progestin therapy for a minimum of 8 weeks were identified. Pre-treatment endometrial biopsy specimens and matched second specimens obtained while on progestin treatment were stained by immunohistochemistry for expression of PR-A, PR-B, pAkt and p4EBP1. The H-score (staining intensity × % of cells) was determined for tumor cells and stroma. T tests were used to compare mean H-scores. Standardized resolution ratios (SRR) were calculated to assess relationship with resolution. Results: 38 subjects were identified with a median age of 36 years (range 23-48). On initial sampling, pathology showed G1EAC in 35% and CAH in 65% of subjects. 50% of subjects had documented resolution to normal histopathology with a median time to resolution of 7 months. Staining for PR-A, PR-B, pAkt and p4EBP1 was found to be positive in 84%, 87%, 84%, and 24% of all patients. The H-score was significantly higher in tumor tissue compared to stromal tissue (p<.0003) for all four markers. PR-A and PR-B expression was significantly decreased in the second specimen under progestin treatment for subjects both with and without resolution (p<.00001). In contrast, pAkt expression decreased significantly after treatment only in subjects with resolution (p = .02). Expression of p4EBP1 did not change significantly with treatment (p = .24). Strong positive PR-A or PR-B staining in tumor tissue of pretreatment biopsies showed a positive correlation with resolution (SRR=1.95, CI 1.15-3.18; SRR = 2.37, CI 1.25-4.13, respectively). In addition, p4EBP1 positivity was associated with resolution (SRR = 2.3, CI 1.48-3.52). Expression of pAkt did not correlate significantly with resolution (SRR = 1.5, CI 0.66-3.29). Conclusions: Our data suggest that the response of premenopausal women with CAH or Grade 1 EA to progestin treatment is significantly correlated with expression of PR-A, PR-B or p4EBP1 in pre-treatment tumor tissue. We propose that the expression of PR-A, PR-B and p4EBP1 may serve as valuable molecular predictors of response to progestin therapy in CAH and Grade 1 EA. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3157. doi:10.1158/1538-7445.AM2011-3157