Abstract P3-11-01: Telapristone acetate suppresses the expression of genes involved in cell proliferation, stem cell self-renewal, and anti-apoptosis in MNU-induced rat mammary tumors
Authors: Lee O , Clare SE , Ivancic D , Scholtens DM , Khan SA 
Published: May 2016

Background: We previously reported that telapristone acetate (TPA), an anti-progestin, significantly suppressed mammary tumor formation and growth accelerated by progesterone (P4) and medroxyprogesterone acetate (MPA) in N-methyl-N-nitrosourea (MNU)-induced carcinogenesis model[1]. This suggests TPA holds promise for the prevention and treatment of human breast cancer. The purpose of this study is to identify the genes modulated by TPA in rat mammary ER/PR+ tumors, which may be translated into a therapeutic biomarker of TPA therapy in ER/PR+ breast cancer.

Methods: Rat mammary tumors from MNU carcinogenesis were used for study [1]. Treatment groups were: control, MPA, P4, MPA+TPA, and P4+TPA. Doses were 30mg of TPA and 25mg of P4 or MPA (90 day release pellets). Tumor epithelium was isolated by laser capture microdissection and RNA extracted. 100 ng of RNA per sample was used for targeted -gene expression profiling by nCounter Gene Expression analysis (Nanostring Inc.). 112 genes related to PR, GR, AR signaling were selected by MetaCore pathway analysis (Thomson Reuters, Inc.). The data was normalized by positive control and RNA content using nSolver. The genes significantly modulated by hormones and TPA were reported as means ± standard deviations (SD) for each group as well as a p-value for pairwise t-test comparison.

Results:

mRNA expression, log mean (log SD).Control vs. P4GeneControlP4pCHD51.5 (0.6)0.7 (0.5)0.03P4 vs. P4+TPAGeneP4P4+TPApSurvivin0.7 (0.5)3.9 (0.2)0.02KI677.6 (0.3)7.1 (0.3)0.02FANCA4.3 (0.2)3.8 (0.3)0.03EZH25.4 (0.2)5.1 (0.2)0.03RFC35.6 (0.2)5.3 (0.2)0.03C.MYC5.9 (0.4)5.5 (0.3)0.04TK15.2 (0.3)4.8 (0.2)0.05Control vs. MPAGeneControlMPApFKBP54.7 (0.4)5.6 (0.6)0.00TNFSF112.0 (0.2)2.8 (0.9)0.02TEK3.7 (0.5)3.1 (0.5)0.03PLZF2.8 (0.9)4.0 (1.1)0.03EPAS15.5 (0.5)4.9 (0.4)0.04MPA vs. MPA+TPAGeneMPAMPA+TPApEGFR6.4 (0.2)6.0 (0.4)0.02SNAI25.0 (0.3)4.6 (0.4)0.04AR4.2 (0.8)5.0 (0.7)0.04Endothelin-15.0 (0.7)3.1 (0.6)0.04

Compared to the control, P4 significantly reduced CHD5 expression, a tumor suppressor in a mouse model, and its down-regulation contributes to the development and progression of human breast cancer. Comparing the P4 and P4+TPA groups, the genes involved in cell proliferation and DNA repair (C-MYC, FANCA, Ki67, RFC3, and TK1), EZH2 (stem cell self-renewal), and anti-apoptosis (survivin) were significantly down-regulated by TPA. On the other hand, MPA induced the up-regulation of FKBP5 (androgen-regulated protein), PLZF (GR responsive gene), TEK (angiogenesis-regulating gene) and TNFSF11 (RANKL) compared to the control. Comparing the MPA and MPA+TPA groups, TPA significantly reduced the expression of EGFR, SNAI2 and endothelin-1 (EMT initiation or maintenance) and increased AR expression.

Conclusions: TPA inhibits P4/PR mediated cell proliferation, and increases apoptosis. The tumorigenic effect of MPA is likely through AR and GR rather than a PR specific manner. In addition to the PR, MPA binds with high affinity to AR and GR, and therefore has the potential to elicit actions distinct to those of P4, which does not bind AR.

[1] Lee O, et al. Cancer Res 2013 vol. 73 no. 24 Supplement P4-11-02.

Citation Format: Lee O, Clare SE, Ivancic D, Scholtens DM, Khan SA. Telapristone acetate suppresses the expression of genes involved in cell proliferation, stem cell self-renewal, and anti-apoptosis in MNU-induced rat mammary tumors. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-11-01.