Cancer Therapy: Preclinical Chloroquine Inhibits Autophagy to Potentiate Antiestrogen Responsiveness in ERþ Breast Cancer

Purpose: Estrogen receptor-a (ERa)-targeted therapies including tamoxifen (TAM) or Faslodex (ICI) are used to treat ERþ 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 ERþ 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 ICIþCQwas less effective than CQ alone in vivo, unlike the TAMþCQ combination. Antiestrogen treatment stimulated angiogenesis in tumors but did not prevent CQ effectiveness. The lower efficacy of ICIþCQwas associatedwith ICI effects on cell-mediated immunity within the tumormicroenvironment. Themouse chemokine KC (CXCL1) and IFNg were differentially regulated by both TAM and ICI treatments, suggesting a possible effect on macrophage development/activity. Consistent with these observations, TAMþCQ treatment increased tumor CD68þ cells infiltration,whereas ICI and ICIþCQreducedperipheral tumormacrophage 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 TAMþCQ suggests a positive outcome for ongoing neoadjuvant clinical trials using this combination for the treatment of ERþ ductal carcinoma in situ lesions. Clin Cancer Res; 20(12);