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

• Published in: Breast cancer research and treatment Vol. 130; no. 2; pp. 437 - 447
• Main Authors: Thomas, Scott, Thurn, Kenneth T., Biçaku, Elona, Marchion, Douglas C., Münster, Pamela N.
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.11.2011; Springer; Springer Nature B.V
• Subjects: Antitumor agents; Apoptosis; Apoptosis - drug effects; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Autophagy; Beclin-1; Biological and medical sciences; Breast cancer; Breast Neoplasms; Cancer cells; Cancer research; Cancer therapies; Care and treatment; Cell Line, Tumor; Cellular biology; Cytochrome c; Drug Synergism; Drug therapy; Estradiol - pharmacology; Estrogen; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; Female; Gene Expression; Gene Knockdown Techniques; Gynecology. Andrology. Obstetrics; Histone Deacetylase Inhibitors - pharmacology; Humans; Hydroxamic Acids - pharmacology; Indoles; Mammary gland diseases; Medical sciences; Medicine; Medicine & Public Health; Membrane Proteins - genetics; Membrane Proteins - metabolism; Microtubule-Associated Proteins - metabolism; Oncology; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases - metabolism; Preclinical Study; Signal Transduction; Tamoxifen; Tamoxifen - pharmacology; Tumors; Valproic Acid - pharmacology; Histone deacetylase; Estrogen receptor; Breast cancer; Anti-estrogen therapy; Autophagy; Apoptosis; Antineoplastic agent; Breast disease; Hormone therapy; Antiestrogen; Estrogen; Antihormone; Selective estrogen receptor modulator; Non steroid compound; Tumor cell; Induction; Malignant tumor; Ovarian hormone; Tamoxifene; Mammary gland diseases; Histone deacetylase inhibitor; Cell death; Sex steroid hormone; Cancer; Hormonal receptor
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-011-1364-y

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.