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Clin Cancer Res. 2014 Jun 15;20(12):3222-32. doi: 10.1158/1078-0432.CCR-13-3227.

Hydroxychloroquine inhibits autophagy to potentiate antiestrogen responsiveness in ER+ breast cancer.

Author information

1
Authors' Affiliations: Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, D.C.; and Department of Pathology, National Cancer Institute, NIH, Bethesda, Maryland.
2
Authors' Affiliations: Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, D.C.; and Department of Pathology, National Cancer Institute, NIH, Bethesda, Maryland clarker@georgetown.edu.

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 hydroxychloroquine (HCQ), 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 HCQ.

RESULTS:

We show that HCQ can increase antiestrogen responsiveness in MCF7-RR and LCC9 cells and tumors, likely through the inhibition of autophagy. However, the combination of ICI+HCQ was less effective than HCQ alone in vivo, unlike the TAM+HCQ combination. Antiestrogen treatment stimulated angiogenesis in tumors but did not prevent HCQ effectiveness. The lower efficacy of ICI+HCQ 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+HCQ treatment increased tumor CD68(+) cells infiltration, whereas ICI and ICI+HCQ reduced peripheral tumor macrophage content. Moreover, macrophage elimination of breast cancer target cells in vitro was reduced following exposure to ICI.

CONCLUSION:

HCQ restores antiestrogen sensitivity to resistant tumors. Moreover, the beneficial combination of TAM+HCQ suggests a positive outcome for ongoing neoadjuvant clinical trials using this combination for the treatment of ER(+) ductal carcinoma in situ lesions.

PMID:
24928945
PMCID:
PMC4073207
DOI:
10.1158/1078-0432.CCR-13-3227
[Indexed for MEDLINE]
Free PMC Article

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