Targeting breast cancer stem cells

Abstract

There is increasing evidence that many cancers, including breast cancer, contain populations of cells that display stem-cell properties. These breast cancer stem cells, by virtue of their relative resistance to radiation and cytotoxic chemotherapy, may contribute to treatment resistance and relapse. The elucidation of pathways that regulate these cells has led to the identification of potential therapeutic targets. A number of agents capable of targeting breast cancer stem cells in preclinical models are currently entering clinical trials. Assessment of the efficacy of the agents will require development of innovative clinical trial designs with appropriate biologic and clinical end points. The effective targeting of breast cancer stem cells has the potential to significantly improve outcome for women with both early-stage and advanced breast cancer.

Fig 1.

Targeting signal transduction pathways in breast cancer stem cells. Schematic illustration of key signal transduction pathways, therapeutic targets, and targeting agents (shown in red). These pathways include Notch; Hedgehog; Wnt; human epidermal growth factor receptor 2 (HER2) –Akt; and cytokine loops, including interleukin (IL) -6 and IL-8.

Fig 2.

Effects of cancer stem cell (CSC) –targeting agents when administered in advanced versus adjuvant settings. (A) Model illustrating hypothetical effect of administration of a selective CSC therapeutic agent in advanced versus adjuvant setting. Only modest effects on tumor size and growth rate are observed when CSC-targeting agent is administered in the advanced setting. In contrast, in the adjuvant setting, eliminating CSCs prevents tumor recurrence. (B) Clinical efficacy of human epidermal growth factor receptor 2 (HER2) blockade in advanced versus adjuvant setting. Hypothetical models illustrate the relationship between HER2 expression in CSC and bulk tumor population and efficacy of HER2 blockade in advanced and adjuvant settings. In tumors classified as HER2-positive (ie, immunohistochemistry [IHC] 3+ or fluorescence in situ hybridization [FISH] positive), HER2 is expressed in both CSC and bulk tumor populations. In these tumors, HER2-targeting agents demonstrate clinical efficacy when administered in both advanced (tumor regression) and adjuvant (reduced recurrence) settings. In tumors currently classified as HER2-negative (ie, IHC1/2+ or FISH negative), HER2 may be selectively expressed in CSC but not bulk cell populations. In these tumors, HER2-targeting agents may be effective when administered in adjuvant but not advanced settings. In contrast, in truly HER2-negative tumors (HER2 0 by IHC), HER2-targeting agents would be predicted to be ineffective in both adjuvant and advanced settings.