| Organic Anion Transporting Polypeptides (OATP) are a family of membrane associated uptake transporters that are expressed in various hormone dependent cancers, including breast cancers. OATP transporters are ubiquitously expressed and transport bile salts, thyroid hormones, steroid hormones and their conjugates, linear and cyclic peptides and xenobiotics. Estrone-3-sulphate (E3S), the predominant source of tumour estrogen for post-menopausal hormone dependent breast cancer patients, is an OATP substrate. There is limited understanding of the role of OATPs in tumour cell uptake of E3S and the potential of these transporters as a novel molecular target. Hence the objectives of this thesis were to determine: i. the differential expression and function of OATP in hormone dependent and independent breast cancers cells, ii. potential of E3S as a targeting ligand for hormone dependent breast tumours and, iii. the clinical expression of OATP in human breast tumour tissues. Expression of OATPs was found to be either exclusive or higher in cancer cells compared to immortalized breast epithelial cells. 10 times greater E3S transport efficiency was observed in hormone dependent breast cancer cells. The in vivo studies conducted in hormone dependent (MCF-7) and independent (MDA-MB-231) xenograft models demonstrated significantly higher (p<0.05) E3S uptake in hormone dependent xenografts [MCF-7: 13.9 +/- 3.1 %ID/g; MDA-MB-231: 10.4 +/- 1.1 %ID/g; at 6 h post injection (p.i.)]. Additionally, the high tumour-to-blood ratios (MCF-7: 7.4+/-1.2; MDA-MB-231: 9.1+/-2.1; at 48 h p.i.), and tumour-to-muscle ratios (MCF-7: 10.7+/-1.5; MDA-MB-231: 3.8+/-0.7; at 6 h p.i.), suggests the potential of E3S as a novel ligand for targeting hormone dependent breast cancers. In the human breast tumour tissue analysis, OATP expression was significantly higher in hormone receptor (HR) positive tumour sections, and highest target signals were obtained from the tumour regions of the tissues. These observations suggest the potential of OATP as a novel molecular target for hormone dependent breast cancers. |
