Coadministration of nanosystems of short silencing RNAs targeting estrogen receptor [alpha] and anti-estrogen synergistically induces tumor growth inhibition in human breast cancer xenografts

• Published in: Breast cancer research and treatment Vol. 122; no. 1; pp. 145 - 158
• Main Authors: Bouclier, Céline, Marsaud, Véronique, Bawa, Olivia, Nicolas, Valérie, Moine, Laurence, Opolon, Paule, Renoir, Jack-michel
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Nature B.V 01.07.2010
• Subjects: Angiogenesis; Breast cancer; Cancer research; Cancer therapies; Estrogens; Ribonucleic acid; RNA
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-009-0558-z

The suppression of estrogen receptor α (ERα) functions by silencing RNAs in association with or not with anti-estrogens (AEs) both in vitro and in breast cancer cell xenografts was assessed. In vitro, a prolonged decrease in ERα protein expression and an enhanced AE-induced inhibition of ERα-mediated transcription, together with antiproliferative activity, were observed. Incorporation of ERα-siRNAs in pegylated nanocapsules (NC) was achieved; and their intravenous injections in MCF-7 xenografts, in contrast to scramble siRNA containing NCs, lead to decrease in ERα protein content and Ki67 labeling in tumor cells. The pure AE RU58668 (RU) both free and entrapped in stealth nanospheres (NS) at very low concentration (8 μg/kg/week) had no effect on tumor growth evolution. However, coinjection of the two nanocarriers potentiated the decrease in ERα protein, concomitantly with decreasing tumor vasculature and glucose transporter-1. These data support that the targeted delivery of ERα-siRNA in breast tumors potentiates the inhibition of E^sub 2^-induced proliferative activity by encapsulated AE through enhanced anti-vascular activity. In the hormone-independent MDA-MB-231 xenograft model, RU-NS at 4 mg/kg/week induce also a strong tumor vascular normalization. Together, these findings suggest that the anti-estrogen activity of RU as well as that of targeted ERα-siRNA leads to anti-angiogenic activity. Their delivery in stealth nanocarriers may constitute a new anti-cancer therapeutic strategy in solid tumors. [PUBLICATION ABSTRACT]