Breast cancer cell targeting by prenylation inhibitors elucidated in living animals with a bioluminescence reporter

Sharon L. Chinault, Julie L. Prior, Kevin M. Kaltenbronn, Anya Penly, Katherine N. Weilbaecher, David Piwnica-Worms, Kendall J. Blumer

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Purpose: Inhibitors of protein prenylation, including prenyltransferase inhibitors and aminobisphosphonates such as zoledronic acid, are being investigated intensively as therapeutics in cancer and other diseases. Determining whether prenylation inhibitors directly or indirectly target tumor and/or host cells is key to understanding therapeutic mechanisms. Experimental Design: To determine which cell types can be targeted directly by distinct classes of prenylation inhibitors in vivo, we describe herein the development and implementation of a sensitive and pharmacologically specific bioluminescence-based imaging reporter that is inducible by prenylation inhibitors. Results: In mouse xenograft models of breast cancer, using reporter-bearing mammary fat pad- or bonelocalized tumor cells, we show that a prenyltransferase inhibitor robustly induces reporter activity in vivo. In contrast, zoledronic acid, a bone-associated aminobisphosphonate that exerts adjuvant chemotherapeutic activity in patients with breast cancer, fails to induce reporter activity in tumor cells of either model. Conclusions: Although a prenyltransferase inhibitor can directly target breast cancer cells in vivo, zoledronic acid and related aminobisphosphonates are likely to exert antitumor activity indirectly by targeting host cells. Accordingly, these findings shift attention toward the goal of determining which host cell types are targeted directly by aminobisphosphonates to exert adjuvant chemotherapeutic activity.

Original languageEnglish
Pages (from-to)4136-4144
Number of pages9
JournalClinical Cancer Research
Volume18
Issue number15
DOIs
StatePublished - Aug 1 2012

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