Macroautophagy Inhibition Sensitizes Tamoxifen-Resistant Breast Cancer Cells and Enhances Mitochondrial Depolarization

Breast Cancer Res Treat. 2008 Dec;112(3):389-403. doi: 10.1007/s10549-007-9873-4. Epub 2008 Jan 3.

Abstract

Macroautophagy (autophagy), a process for lysosomal degradation of organelles and long-lived proteins, has been linked to various pathologies including cancer and to the cellular response to anticancer therapies. In the human estrogen receptor positive MCF7 breast adenocarcinoma cell line, treatment with the endocrine therapeutic tamoxifen was shown previously to induce cell cycle arrest, cell death, and autophagy. To investigate specifically the role of autophagy in tamoxifen treated breast cancer cell lines, we used a siRNA approach, targeting three different autophagy genes, Atg5, Beclin-1, and Atg7. We found that knockdown of autophagy, in combination with tamoxifen in MCF7 cells, results in decreased cell viability concomitant with increased mitochondrial-mediated apoptosis. The combination of autophagy knockdown and tamoxifen treatment similarly resulted in reduced cell viability in the breast cancer cell lines, estrogen receptor positive T-47D and tamoxifen-resistant MCF7-HER2. Together, these results indicate that autophagy has a primary pro-survival role following tamoxifen treatment, and suggest that autophagy knockdown may be useful in a combination therapy setting to sensitize breast cancer cells, including tamoxifen-resistant breast cancer cells, to tamoxifen therapy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antineoplastic Agents, Hormonal / pharmacology*
  • Apoptosis
  • Autophagy*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism*
  • Cell Line, Tumor
  • Cell Survival
  • Drug Resistance, Neoplasm*
  • Flow Cytometry
  • Gene Silencing
  • Humans
  • Lysosomes / metabolism
  • Microscopy, Fluorescence / methods
  • Mitochondria / metabolism*
  • RNA, Small Interfering / metabolism
  • Tamoxifen / pharmacology*

Substances

  • Antineoplastic Agents, Hormonal
  • RNA, Small Interfering
  • Tamoxifen