Abstract 2146: The chemo-preventive effect of ER-β agonist on DMBA induced breast cancers

Abstract

Abstract Introduction: ER-beta (ER-β) regulates genes involved in cellular proliferation and apoptosis, and is considered to be anti-proliferative and tumor suppressive. ER-β is frequently reduced or lost in breast cancers (BrC). ER-β can also transdominantly inhibit ER-α transcription at some genes, even in the absence of ligand. Thus, ER-β selective agonists such as diarylpropionitrile (DPN) may inhibit breast cancer cells, and may also prevent tumor initiation or tumor growth of BrC through lowering proliferation and higher apoptosis. Methods: A total of 49 Sprague-Dawley rats (19 ovariectomized (OVX) and 30 non-OVX) were treated with DMBA breast cancer carcinogen. Then the rats were separated into two groups. In the first group, the rats received daily DPN injections (1000ug/kg BW) starting immediately after DMBA administration, to observe tumor prevention or initiation. In the second, only the rats developed tumor(s) ≥ 1cm received daily DPN, to observe reduction or increase of tumor sizes. The rats were sacrificed to collect tumors and normal breast tissues, which were tested for H&E, mRNA, and ER-α, ER-β, and Cyclin D1 expression by immunohistochemistry. Cyclin D1 staining was evaluated to determine the effect of DPN on tumor and normal breast ductal cell proliferation. Results: In spite of DMBA administration, none of the OVX rats developed breast tumors during the experiment. However, 70% of the non-OVX rats developed BrC, with the majority of the tumors in the 7th week after DMBA, with multiple tumors in the same animal. The rats that developed tumors and subsequently received DPN showed slight retardation of tumor growth in the first 2 weeks, but ultimately tumor growth was not inhibited. On the other hand, rats received DPN immediately with DMBA showed delayed tumor initiation at 11 weeks, and only 25% of the rats developed one small tumor. ER-α mRNA of tumor tissues in both experiments was up-regulated and ER-β was down-regulated, with an ER-α:ER-β ratio of 10-100:1. However, ER-β protein was expressed in more than 60% of tumor tissues. Cyclin D1 staining in normal breast tissues and tumor cells were 40% and 70-95% respectively, but tumor tissues from the rats that received immediate DPN injections showed decreased Cyclin D1 staining ranging from 10 to 50%. Conclusion: ER-β-selective agonist DPN, when injected daily starting immediately after DMBA administration, can inhibit tumor induction and may be chemo-preventive. However, when tumors have already developed and reached ≥ 1cm, and ERβ is reduced or lost in tumor cells, DPN does not have any effect on prevention or inhibition of tumor growth. It appears that early loss or reduction of ERβ signaling may in turn contributes to excessive cell proliferation and neoplastic transformation. Our study also confirms that depletion of estrogen through OVX inhibits tumor initiation. This is a preliminary data from our ongoing studies with additional ERβ agonists to test a larger group of rats. Note: This abstract was not presented at the meeting. Citation Format: Young J. Choi, Yehwang Cheong. The chemo-preventive effect of ER-β agonist on DMBA induced breast cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2146. doi:10.1158/1538-7445.AM2014-2146