Breast Cancer Research and Treatment

, Volume 130, Issue 2, pp 437–447 | Cite as

Addition of a histone deacetylase inhibitor redirects tamoxifen-treated breast cancer cells into apoptosis, which is opposed by the induction of autophagy

  • Scott Thomas
  • Kenneth T. Thurn
  • Elona Biçaku
  • Douglas C. Marchion
  • Pamela N. Münster
Preclinical study

Abstract

Modulation of estrogen signaling is one of the most successful modalities for the treatment of estrogen receptor (ER)-positive breast cancer, yet de novo and acquired resistance are frequent. Recent data suggests that the induction of autophagy may play a considerable role in promoting tumor cell survival and resistance to anti-estrogen therapy. Hence, bypassing autophagy may offer a novel strategy to enhance the anti-tumor efficacy of anti-estrogens. Histone deacetylases (HDAC) are involved in the regulation of steroid hormone receptor mediated cell signaling and their inhibition potentiates the anti-tumor effects of anti-estrogens. However, the mechanism underlying this anti-tumor activity is poorly understood. In this report, we show that the addition of an HDAC inhibitor redirects the response of ER-positive breast cancer cells when treated with tamoxifen from growth arrest to apoptotic cell death. This redirection requires functional ER signaling and is mediated by a depletion of Bcl-2 and an induction of Bax and Bak, manifesting in cytochrome C release and PARP cleavage. With combined treatment, a subpopulation of cells is refractory to apoptosis and exhibit a strong induction of autophagy. Inhibition of autophagy in these cells, using siRNA directed against Beclin-1 or treatment with chloroquine, further promotes the induction of apoptosis. Thus, supporting prior reports that autophagy acts as a survival mechanism, our findings demonstrate that HDAC and autophagy inhibition directs autophagy-protected cells into apoptotic cell death, which may impair development of tamoxifen resistance.

Keywords

Breast cancer Histone deacetylase Anti-estrogen therapy Estrogen receptor Autophagy Apoptosis 

Abbreviations

HDAC

Histone deacetylase

ER

Estrogen receptor

siRNA

Small interfering RNA

VPA

Valproic acid

Supplementary material

10549_2011_1364_MOESM1_ESM.tiff (5.5 mb)
Supplemental Figure 1. HDAC inhibitors potentiate the cytotoxicity of tamoxifen in T47D cells. T47D cells were treated with vehicle, C, 0.5 mM VPA, V, 10 μM 4OH-tamoxifen, T, or 0.5 mM VPA and 10 μM 4OH-tamoxifen, VT, and assayed for viability by dye exclusion assay (A) or apoptosis by scoring condensed and fragmented nuclei (B) at the indicated times. For viability and apoptosis, each condition was conducted in triplicate and presented as the average with error bars indicating the standard error of the mean. (TIFF 5680 kb)

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Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Scott Thomas
    • 1
  • Kenneth T. Thurn
    • 1
  • Elona Biçaku
    • 2
  • Douglas C. Marchion
    • 2
  • Pamela N. Münster
    • 1
  1. 1.Division of Hematology and OncologyUniversity of CaliforniaSan FranciscoUSA
  2. 2.H. Lee Moffitt Cancer Center and Research InstituteTampaUSA

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