Abstract 3444: The effect of IGFs on ERβ isoforms: Potential targets in TNBC

Abstract

Abstract Breast cancer is the most common cancer among women in the world (Parkin et al. 2005). The current classification of breast cancer recognizes four categories: ER+/PR+/HER-2-, ER+/PR+/HER+, ER-/PR-/HER-2+, and ER-/PR-/HER-2- referred to as triple negative breast cancer (TNBC). The last two categories comprise tumors with a more aggressive behavior and poorer prognosis (Davidson et al. 1992). With the discovery of Estrogen Receptor Beta (ERβ) in 1996 the definition of ER status has become more complex. ERβ is not only expressed in both normal and malignant breast tissues (Jarvinen et al. 2000), but is expressed in 50-90% of all ER- breast cancers (Skliris et al. 2006). When co-expressed, ERβ counteracts the proliferative function of ERα, however the role of ERβ in ER- is unclear. Multiple variant isoforms of ERβ have been identified and shown to be expressed differentially in human breast cancer (Chi et al. 2003). However the exact role of ERβ isoforms in human breast cancer, especially TNBC remains elusive. Insulin-like growth factors (IGFs) stimulate cell proliferation and promote cell survival in triple-negative breast cancer cells (Davison et al. 2011). IGF-I and II both play an important role in fetal growth, however after gestation IGF-II levels decrease significantly while IGF-I continues to have anabolic effects in adults (Keating 2008). Both play a major role in cancer development. Our lab has demonstrated that women with more aggressive tumors and poorer prognoses have increased levels of IGF-II coupled with lower levels of the IGF-IIR needed for degradation of IGF-II (Singh et al. 2011) We have also shown that IGF-II activates ERα and ERβ in the absence of the estrogen ligand (Richardson et. Al 2011). Since certain ERβ, namely ERβ1, 2 and 5, are so highly expressed in aggressive cancers and IGF-II activates ERβ, we hypothesize that IGF-II will have a potent effect on ERβ isoforms transcription in our TNBC cell lines (MDA-MB 231, CRL 2335, and HS-578T when compared to ER+ cell line MCF-7) We believe that the aggressiveness of TNBC is based on the increased expression and activity of ERβ isoforms. To test this hypothesis we characterized the levels of total IGF-I and IGF-II as well as ERβ isoforms 1, 2 and 5 at the level of mRNA before and after IGF-I and IGF-II treatment. We also characterized the levels of IGF-I, IGF-II and total ERβ and isoform 5 at the protein level before and after treatment. The stable knockdown of IGF-II (2335aS) decreased the transcript levels of all of the ERβ isoforms, while over-expression of IGF-II (MCF-7LS) increased the levels of ERβ isoform 5 protein significantly when compared to the wild-type. We propose that the potential role of the ERβ isoforms in TNBC is to impair the inhibitory function of ERβ1thus promoting cellular proliferation and tumor development. Citation Format: Chane' O'Bannon-Joseph, Daisy D. DeLeon. The effect of IGFs on ERβ isoforms: Potential targets in TNBC. [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 3444. doi:10.1158/1538-7445.AM2014-3444