Dietary Chemopreventative Benzyl Isothiocyanate Inhibits Breast Cancer Stem Cells In Vitro and In Vivo

Menée in vitro et à l'aide de xénogreffes, cette étude montre que l'isothiocyanate de benzyle, une molécule présente dans les végétaux crucifères, peut inhiber le développement des cellules souches du cancer du sein

Résumé en anglais

A small subset of mammary tumor initiating cells (also known as breast cancer stem cells; bCSC), characterized by expression of different markers [CD44high/CD24low/epithelial specific antigen(ESA)+], aldehyde dehydrogenase-1 (ALDH1) activity, and ability to form mammospheres under ultra-low attachment culture conditions, are suspected to evade conventional therapies leading to disease recurrence. Elimination of both therapy-sensitive epithelial tumor cells and therapy-resistant bCSC is therefore necessary for prevention of breast cancer. We have shown previously that a nontoxic small-molecule constituent of edible cruciferous vegetables (benzyl isothiocyanate; BITC) inhibits mammary cancer development in mouse mammary tumor virus-neu (MMTV-neu) transgenic mice by causing epithelial tumor cell apoptosis. The present study demonstrates efficacy of BITC against bCSC in vitro and in vivo. Mammosphere formation frequency and CD44high/CD24low/ESA+ and/or ALDH1+ populations in cultured MCF-7 (estrogen-receptor positive) and SUM159 (triple-negative) human breast cancer cells were decreased significantly in the presence of plasma achievable concentrations of BITC. BITC administration in the diet (3 μmol BITC/g diet for 29 weeks) resulted in a marked decrease in bCSC in the MMTV-neu mice tumors in vivo. Overexpression of full-length Ron as well as its truncated form (sfRon), but not urokinase-type plasminogen activator receptor, conferred near complete protection against BITC-mediated inhibition of bCSC in MCF-7 cells. The BITC treatment downregulated protein levels of Ron and sfRon in cultured breast cancer cells and in tumor xenografts. Ron overexpression resulted in up-regulation of bCSC-associated genes Oct-4, SOX-2, and Nanog. In conclusion, the present study indicates that BITC treatment eliminates bCSC in vitro and in vivo.