The Natural Product Sulforaphane Inhibits Breast Cancer Stem Cell Targets in Triple Negative and Trastuzumab-resistant Breast Cancers.

Abstract

The cancer stem cell (CSC) hypothesis provides a hierarchical model which explains the observed heterogeneity of cancers cells within a tumor. CSCs sit at the apex of the tumor hierarchy and are uniquely capable of initiating tumor formation. These cells retain two key properties: self-renewal, which allows for long term proliferation potential and the capability to differentiate into the heterogeneous cell lineages found within a tumor. In order to truly cure patients it is necessary to not only reduce tumor volume but eliminate all cell populations within the cancer. Accumulating evidence suggests that breast cancers are driven by CSCs and that this model can address two critical needs associated with drug resistance in patients to improve overall survival. In this report we demonstrate that in triple negative breast cancers (TNBCs) current chemotherapy fails to eliminate, and may even expand, breast CSCs through activation of the NF-kB signaling node. Similarly, we demonstrate in HER2+ breast cancers with PTEN inactivation that the generation of trastuzumab resistance results in the dependence on an IL6/STAT3/NF-kB positive feedback loop. Activation of this signaling loop induced the epithelial to mesenchymal transition, expanded BCSCs, and results in a subtype conversion from HER2+ to TNBC. In these contexts, current treatment strategies are simply delaying disease progression rather than attacking the roots of breast cancer. Using the natural product sulforaphane (SF) which has been demonstrated to inhibit NF-kB signal transduction, we demonstrate that this compound can be used to address these issues. In this report SF preferentially inhibited TNBC cell lines and CSCs. Due to its inhibition of NF-kB, SF reduced IL6-mediated BCSC expansion induced by docetaxel treatment. Consequently, combination of the two therapies dramatically reduced both tumor volume and CSCs. In trastuzumab resistant, PTEN deficient, breast cancers NF-kB inhibition by SF was sufficient to eliminate both of these populations. By analyzing the transcriptional landscape of trastuzumab sensitive and resistant cell lines in the presence of SF with RNA sequencing, MEOX1 was identified as a novel drug target capable of regulating bulk cell line proliferation and breast CSC self-renewal in trastuzumab resistant breast cancer and a subset of TNBCs.