Abstract 3929: Estrone-3-sulphate, a potential novel ligand for targeting breast cancers.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC This study investigates the potential of estrone-3-sulphate (E3S) as a ligand for targeting Organic Anion Transporting Polypeptides (OATP), a family of membrane-associated transport proteins, for detection of hormone dependent breast cancers. E3S, a circulating inactive plasma estrogen, is an OATP substrate and a predominant source of tumour estradiol in post-menopausal patients. It has been reported that some of the OATP isoforms (e.g. OATP1A2, OATP2B1) are over expressed (up to ten times) in breast cancer tissues as compared to surrounding normal tissues. This suggests that the two- three times higher E3S concentration reported in malignant tissues, as compared to the surrounding normal tissues, could be due to higher expression and/or increased functional activity of OATPs detected in breast tumour tissues. We recently demonstrated in vitro that expression of some of the OATPs (i.e. OATP1A2, OATP1B1, OATP1B3, OATP1C1, OATP2B1, OATP3A1 and OATP4A1) were either exclusive, similar or significantly higher (p<0.001) in breast cancer cells as compared to normalized breast epithelial cells (MCF10A). Thus to assess in vivo, the potential of E3S as a ligand for targeting OATPs in breast cancers, distribution of exogenous E3S (administered intravenously) was determined in murine models of hormone-dependent (MCF-7) and independent (MDA-MB-231) breast cancers. The highest levels of tumour uptake were observed at 6h post injection (p.i) with significant difference between the level in MCF-7 (13.9 ± 3.1 %ID/g) and MDA-MB-231 (10.4 ± 1.1 %ID/g). The highest tumour-to-blood ratios (MCF-7: 7.4±1.2; MDA-MB-231: 9.1±2.1) were observed at 48 p.i., and highest tumour-to-muscle ratios (MCF-7: 10.7±1.5; MDA-MB-231: 3.8±0.7) were observed at 6h p.i. Analogous to total tumour uptake, ex vivo tumour cell uptake at 2h p.i. was 6 fold higher in MCF-7 compared to MDA-MB-231 tumour cells. Blocking studies, conducted by pre-administration of 100-fold excess E3S, resulted in significantly lower tumour uptake in both xenograft models, suggesting the involvement of an active carrier mediated process. Immunohistochemical analysis detected OATP1A2 in tumour sections from both xenografts, with significantly higher expression in the MCF-7 xenografts. Overall, the higher tumour uptake and tumour-to-muscle ratio, alongside the higher expression of OATP1A2, in the MCF-7 xenograft model suggest the potential of E3S to serve as a novel ligand for targeting hormone dependent breast cancers. To the best of our knowledge, this is the first report documenting the in vivo distribution of exogenous E3S, in models of hormone dependent and independent breast cancers. Citation Format: Nilasha Banerjee, Humphrey Fonge, Andrew Mikhail, Raymond M. Reilly, Reina Bendayan, Christine Allen. Estrone-3-sulphate, a potential novel ligand for targeting breast cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3929. doi:10.1158/1538-7445.AM2013-3929