title: Targeted elimination of breast cancer cells with low proteasome activity is sufficient for tumor regression.
abstract: Breast cancers are thought to be organized hierarchically with a small number of breast cancer stem cells (BCSCs), able to regrow a tumor after sublethal treatment while their progeny lack this feature. Furthermore, BCSCs are highly resistant to conventional anticancer treatments. According to the cancer stem cell hypothesis, all cancer stem cells in a tumor have to be eliminated to achieve cancer cure. In this study we tested if targeted elimination of BCSCs leads to tumor regression. Specific targeting of BCSCs was achieved via a unique imaging and targeting system that relies on their low proteasome activity. In our system breast cancer cells stably express a fluorescent fusion protein, thymidine kinase-ZsGreen-cODC, which is readily degraded after translation in cells with normal 26S proteasome activity. However, cells with low proteasome activity accumulate this fluorescent fusion protein, thus allowing for their identification, tracking, and specific elimination. Here, we show that the activity of the 26S proteasome was significantly down-regulated in MCF-7, T47D, and MDA-MB-231 cultures enriched for BCSCs. Treatment with ganciclovir resulted in abrogation of sphere formation in vitro, and tumor regression in vivo, thus demonstrating that targeted elimination of BCSCs leads to loss of self-renewal in vitro and tumor regression in vivo. We conclude that specific targeting of BCSCs could be a useful strategy to improve treatment outcome.
authors.affiliation: Department of Radiation Oncology, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Los Angeles, CA, 90095-1714, USA.
authors.forename: Erina
authors.initials: E
authors.lastname: Vlashi
authors.forename: Chann
authors.initials: C
authors.lastname: Lagadec
authors.forename: Mabel
authors.initials: M
authors.lastname: Chan
authors.forename: Patricia
authors.initials: P
authors.lastname: Frohnen
authors.forename: Alexandra Jean
authors.initials: AJ
authors.lastname: McDonald
authors.forename: Frank
authors.initials: F
authors.lastname: Pajonk
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015536:Down-Regulation; D004789:Enzyme Activation; D005260:Female; D064593:Heterografts; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D018874:Spheroids, Cellular; D047368:Tumor Burden; D014407:Tumor Cells, Cultured
chemical_list: D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease