Downregulation of Aurora-A overrides estrogen-mediated growth and chemoresistance in breast cancer cells

• Published in: Endocrine-related cancer Vol. 15; no. 3; pp. 765 - 775
• Main Authors: Lee, Heng Hong, Zhu, Yansong, Govindasamy, Karthik M, Gopalan, Ganesan
• Format: Journal Article
• Language: English
• Published: England Society for Endocrinology 01.09.2008; BioScientifica
• Subjects: Antineoplastic Agents - pharmacology; Aurora Kinase A; Aurora Kinases; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Adhesion - drug effects; Cell Proliferation - drug effects; Down-Regulation - drug effects; Down-Regulation - physiology; Drug Resistance, Neoplasm - drug effects; Estradiol - adverse effects; Estradiol - pharmacology; Estrogen Receptor alpha - physiology; Humans; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - metabolism; RNA, Small Interfering - pharmacology; Taxoids - pharmacology; Tumor Cells, Cultured
• ISSN: 1351-0088; 1479-6821
• DOI: 10.1677/ERC-07-0213

Estrogen is known to play a causative role in the development of sporadic breast cancers and chemoresistance. However, studies on the mechanism and proteins involved in mediating the oncogenic effects of estrogen are very limited. Recently, Aurora-A, a centrosomal protein kinase, which induces centrosome amplification and genomic instability, has been shown to be upregulated during long-term treatment of rats with estrogen and was implicated in estrogen-induced oncogenesis. Herein, we present results of the studies carried out in short-term in vitro cultures to understand the regulation of Aurora-A by estrogen and the effect of downregulation of Aurora-A on estrogen-induced breast tumorigenesis and chemoresistance. Treatment of breast cancer cells with 10 nM 17β-estradiol (E2) resulted in the upregulation of Aurora-A levels in an estrogen receptor-dependent manner. However, the upregulation by E2 was not restricted to Aurora-A alone. Following release from the tamoxifen-induced arrest, the appearance of Aurora-A in the presence of estradiol in MCF7 cells coincided with the appearance of other mitotic markers suggesting that the spike in Aurora-A levels is an indirect consequence of estrogen-mediated cell proliferation. Thus, at least in short-term in vitro studies, Aurora-A is not a specific direct target of estrogen. However, downregulation of Aurora-A by RNA interference led to a significant decrease in estrogen-induced, anchorage-dependent, and independent growth of MCF7 cells. Moreover, knockdown of Aurora-A could overcome estrogen-induced decrease in docetaxel sensitivity of MCF7 cells. Cumulatively, we propose that the upregulation of Aurora-A by estrogen in short-term in vitro cultures is an indirect consequence of estrogen-induced cell proliferation. Nevertheless, Aurora-A inhibitors could be exploited to override the effects of estrogen on breast tumorigenesis and chemoresistance.