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

Abstract

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 17b-estradiol (E 2 ) resulted in the upregulation of Aurora-A levels in an estrogen receptordependent manner. However, the upregulation by E 2 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.

Growth inhibition and enhanced chemosensitivity induced by down-regulation of Aurora-A in human renal cell carcinoma Caki-2 cells using short hairpin RNA

“…Taken together, these findings indicate that the synergistic induction of apoptosis in cancer cells may be achieved by the suppression of Aurora-A expression combined with the use of docetaxel. Similarly, the enhancement of docetaxel-induced apoptosis by the inhibition of Aurora-A expression using a variety of cancer cell lines, such as head and neck, esophageal and breast cancer cell lines has also been reported (20)(21)(22).…”

HIF-1 is involved in the negative regulation of AURKA expression in breast cancer cell lines under hypoxic conditions

“…Since AURKA is a key regulator of the chromosomal segregation process in mammalian cells and its down-regulation overrides the estrogen-mediated growth and chemoresistance in BC cells [53], these results could provide innovative approaches for the development of novel possible therapeutic strategies against BC.…”

Aurora kinase A inhibition-induced autophagy triggers drug resistance in breast cancer cells

“…[6][7][8] Moreover, high AURKA expression induces chemoresistance in breast cancer cells and ovarian cancer cells. 9,10 Our previous studies suggest that targeting AURKA may be of therapeutic use, leading to apoptosis in acute myeloid leukemia and tongue squamous cell carcinoma. 11,12 Therefore, AURKA is considered a promising molecular target for cancer therapy.…”