Title

The HDAC Inhibitor LBH589 Reduces Cell Proliferation in Breast Cancer Cell Lines including those Resistant to Aromatase Inhibitors

Authors

Molly Storer

Document Type

Article

Publication Date

2010

Abstract

In the U.S., 1 in 6 women will develop breast cancer. Major treatments for breast cancer are surgery, chemo-therapy, radiation and hormone therapy. The most widely used hormone therapy in clinic is a class of drugs called aromatase inhibitors (AI) that block the function of the enzyme aromatase [3]. Aromatase is the enzyme that converts androgen to estrogen, and blocking the aromatase pathway has been an effective treatment for hormone dependent breast cancers [2]. Hormone dependent breast cancer is the most common form of breast cancer in post menopausal women, and it is characterized by the overproduction of estrogen levels within the cancer cells. While AI treatment has been clinically effective at eradicating breast cancer, resistance to these therapies sometimes occurs, and it leads to relapse in many patients [2]. This is a great clinical problem. LBH589 is a histone deacetylase inhibitor whose design upregulates gene expression. This drug was previously used to treat lymphoma, and it was well tolerated by patients in clinical trials [1]. Microarray analysis revealed LBH589 actually downregulates some gene expression [1]. So, although this drug is safe for patients, the mechanism of its effectiveness remains a mystery. Our lab has developed cell lines resistant to third generation AIs such as Letrozole, Anastrozole, and Exemestane [2]. Our objective is to test whether LBH589 is effective in inhibiting cell proliferation in AI resistant cell lines. The clinical significance of this research is great, and it will provide a potential solution to patients whose breast cancers have become resistant to AI therapy. Cells in triplicate were treated in 96-well plates with LBH589 and an MTT assay was preformed to track cell proliferation at baseline, 24, 48 and 72 hours after treatment. Cells treated with LBH589 showed a dose dependent inhibitory cell proliferation response in all cell lines. Ana-R, an AI resistant breast cancer cell line, was most sensitive to the LBH589 treatment. While LBH589 effectively reduces cell proliferation in resistant cell lines, its effects are most potent in the Ana-R cell line. 1.) Chen, Shiuan, Jingjing Ye, Ikuko Kijima, and Dean Evans. "The HDAC inhibitor LBH589 (panobinostat) is an inhibitory modulator of aromatase gene expression." PNAS 107 (2010): 11032-37. Print. 2.) S.Chen et. Al, ?New experimental models for aromatase inhibitor resistance? Journal of Steriod Biochemistry & Molecular Biology 106 (2007) 8-15 3.) Lonning. P.E. ?The potency and clinical efficacy of aromatase inhibitors across the breast cancer continuum? Annals of Oncology (2010)

Advisor

Dr. Shiuan Chen and Dr. Noriko Kanaya, City of Hope

Department

bio

Support

Howard Hughes Medical Institute Undergraduate Science Education Grant

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