TY - JOUR
T1 - Progesterone receptor antagonism inhibits progestogen-related carcinogenesis and suppresses tumor cell proliferation
AU - Lee, Oukseub
AU - Choi, Mi Ran
AU - Christov, Konstantin
AU - Ivancic, David
AU - Khan, Seema A.
N1 - Funding Information:
This work was supported by Breast Cancer Research Foundation for the MNU/rat study and spheroid experiment and Lynn Sage Cancer Research Foundation for the DMBA/mouse study. The authors would like to thank Repros Therapeutics, Inc., and HRA-Pharma (Paris, France) for providing materials and other support. The authors had full responsibility for the design of the study, the collection of the data, the analysis and interpretation of the data, the writing of the manuscript, and the decision to submit the manuscript for publication.
Publisher Copyright:
© 2016 Elsevier Ireland Ltd.
PY - 2016/7/1
Y1 - 2016/7/1
N2 - Purpose: Blockade of the progestogen-progesterone receptor (PR) axis is a novel but untested strategy for breast cancer prevention. We report preclinical data evaluating telapristone acetate (TPA), ulipristal acetate (UPA), and mifepristone. Methods: Tumors were induced with medroxyprogesterone acetate (MPA) plus 7,12-dimethylbenz[a]anthracene (DMBA) in mice, and MPA or progesterone plus N-methyl-N-nitrosourea (MNU) in rats. Mammary gland histology, tumor incidence, latency, multiplicity, burden and histology were evaluated, along with immunohistochemical labeling of pHH3 (proliferation), CD34 (angiogenesis), and estrogen and progesterone receptors (ER and PR). A concentration gradient of TPA, UPA, and mifepristone was tested for growth inhibition of T47D spheroids. Results: In mouse mammary glands, no tumors formed, but TPA opposed the pro-hyperplastic effects of MPA (p = 0.002). In rats, TPA decreased tumor incidence (p = 0.037 for MPA + TPA vs. MPA, and p = 0.032 for progesterone + TPA vs. progesterone) and tumor burden (p = 0.042 for progesterone + TPA vs. progesterone), with significant decreases in pHH3 and CD34 positive cells. TPA and UPA were superior to mifepristone in growth inhibition of T47D spheroids. Conclusion: TPA has consistent anti-tumorigenic effects in several models, which are accompanied by decreases in cell proliferation, angiogenesis, and hormone receptor expression.
AB - Purpose: Blockade of the progestogen-progesterone receptor (PR) axis is a novel but untested strategy for breast cancer prevention. We report preclinical data evaluating telapristone acetate (TPA), ulipristal acetate (UPA), and mifepristone. Methods: Tumors were induced with medroxyprogesterone acetate (MPA) plus 7,12-dimethylbenz[a]anthracene (DMBA) in mice, and MPA or progesterone plus N-methyl-N-nitrosourea (MNU) in rats. Mammary gland histology, tumor incidence, latency, multiplicity, burden and histology were evaluated, along with immunohistochemical labeling of pHH3 (proliferation), CD34 (angiogenesis), and estrogen and progesterone receptors (ER and PR). A concentration gradient of TPA, UPA, and mifepristone was tested for growth inhibition of T47D spheroids. Results: In mouse mammary glands, no tumors formed, but TPA opposed the pro-hyperplastic effects of MPA (p = 0.002). In rats, TPA decreased tumor incidence (p = 0.037 for MPA + TPA vs. MPA, and p = 0.032 for progesterone + TPA vs. progesterone) and tumor burden (p = 0.042 for progesterone + TPA vs. progesterone), with significant decreases in pHH3 and CD34 positive cells. TPA and UPA were superior to mifepristone in growth inhibition of T47D spheroids. Conclusion: TPA has consistent anti-tumorigenic effects in several models, which are accompanied by decreases in cell proliferation, angiogenesis, and hormone receptor expression.
KW - Mammary carcinogenesis
KW - Prevention
KW - Progesterone receptor
KW - Progestogen
KW - Rats
KW - Telapristone acetate
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U2 - 10.1016/j.canlet.2016.04.010
DO - 10.1016/j.canlet.2016.04.010
M3 - Article
C2 - 27080304
AN - SCOPUS:84963624378
VL - 376
SP - 310
EP - 317
JO - Cancer Letters
JF - Cancer Letters
SN - 0304-3835
IS - 2
ER -
