The natural product sulforaphane (SF) has demonstrated efficacy against multiple forms of cancers and cancer stem cells. However, it is unclear what are the molecular targets for sulforaphane to inhibit breast cancer stem cells and how efficacy varies among four subtypes of breast cancers. In vitro assay showed that sulforaphane preferentially inhibited triple negative (TNBC) breast cancers, but did not show any efficacy to inhibit Her2+ breast cancer cells (even at >100 uM). However, when Her2+ breast cancer cells (with PTEN deletion) developed resistance to trastuzumab, sulforaphane showed more than 20-fold higher activity. Low concentration of sulforaphane (1 uM) also preferentially eliminates breast cancer stem cells from triple negative breast cancers. Her2+ breast cancer cells (with PTEN deletion and long term treatment of trastuzumab) induced resistance to trastuzumab and increase breast cancer stem cell populations by activating a positive feedback loop of IL-6 and NF-kB. Luciferase reporter assay and immunostaining showed that sulforaphane (1 uM) disrupted NF-kB translocation from cytosol to nucleus and inhibited its activity. Sulforaphane (1 uM) also inhibited endogenous IL-6 production by 50%. Sulforaphane (50 mg/kg, adjuvant therapy) reduced tumor formation rate by 70% and inhibit tumor volume by more than 90% of trastuzumab resistant Her2+ breast cancers in mouse fat pad. These data suggest that sulforaphane inhibits trastuzumab-resistant Her2+ breast cancers and breast cancer stem cells by disrupting NF-kB and IL6 positive feedback loop.
Citation Format: Joseph Burnett, Hasan Korkaya, Bryan Newman, Sarah Conley, Jamie Connarn, Lichao Sun, Hsiu-Fang Lee, Maria Ouzounova, Max Wicha, Duxin Sun. Natural product sulforaphane selectively inhibits breast cancer stem cells in basal and trastuzumab resistant Her2+ breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 913. doi:10.1158/1538-7445.AM2013-913