Circulating mouse cytokine and chemokine involvement. A. Interferon-γ and TNFÎ{plus minus} were measured by ELISA in plasma from mice treated with control, CQ, ICI, ICI+CQ, TAM, and TAM+CQ. n=3-6
ARTICLE ABSTRACT
Purpose: Estrogen receptor-α (ERα)-targeted therapies including tamoxifen (TAM) or Faslodex (ICI) are used to treat ER+ breast cancers. Up to 50% of tumors will acquire resistance to these interventions. Autophagy has been implicated as a major driver of antiestrogen resistance. We have explored the ability of chloroquine (CQ), which inhibits autophagy, to affect antiestrogen responsiveness.Experimental Design: TAM-resistant MCF7-RR and ICI-resistant/TAM cross-resistant LCC9 ER+ breast cancer cells were injected into mammary fat pads of female athymic mice and treated with TAM and/or ICI in combination with oral low-dose CQ.Results: We show that CQ can increase antiestrogen responsiveness in MCF7-RR and LCC9 cells and tumors, likely through the inhibition of autophagy. However, the combination of ICI+CQ was less effective than CQ alone in vivo, unlike the TAM+CQ combination. Antiestrogen treatment stimulated angiogenesis in tumors but did not prevent CQ effectiveness. The lower efficacy of ICI+CQ was associated with ICI effects on cell-mediated immunity within the tumor microenvironment. The mouse chemokine KC (CXCL1) and IFNγ were differentially regulated by both TAM and ICI treatments, suggesting a possible effect on macrophage development/activity. Consistent with these observations, TAM+CQ treatment increased tumor CD68+ cells infiltration, whereas ICI and ICI+CQ reduced peripheral tumor macrophage content. Moreover, macrophage elimination of breast cancer target cells in vitro was reduced following exposure to ICI.Conclusion: CQ restores antiestrogen sensitivity to resistant tumors. Moreover, the beneficial combination of TAM+CQ suggests a positive outcome for ongoing neoadjuvant clinical trials using this combination for the treatment of ER+ ductal carcinoma in situ lesions. Clin Cancer Res; 20(12); 3222–32. ©2014 AACR.
