Macroautophagy inhibition sensitizes tamoxifen-resistant breast cancer cells and enhances mitochondrial depolarization

• Published in: Breast cancer research and treatment 2008-12, Vol.112 (3), p.389-403
• Main Authors: Qadir, M. A., Kwok, B., Dragowska, W. H., To, K. H., Le, D., Bally, M. B., Gorski, Sharon M.
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Antineoplastic Agents, Hormonal - pharmacology; Apoptosis; Autophagy; Biological and medical sciences; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Cancer research; Cancer therapies; Cell Line, Tumor; Cell Survival; Cellular biology; Chemotherapy; Drug resistance; Drug Resistance, Neoplasm; Flow Cytometry; Gene Silencing; Gynecology. Andrology. Obstetrics; Humans; Lysosomes - metabolism; Mammary gland diseases; Medical sciences; Medicine; Medicine & Public Health; Microscopy, Fluorescence - methods; Mitochondria - metabolism; Oncology; Pharmacology. Drug treatments; Preclinical Study; RNA, Small Interfering - metabolism; Tamoxifen - pharmacology; Tumors
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-007-9873-4

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.