Departments of Experimental Radiation Oncology, University of Texas, MD Anderson Cancer Center, Houston, Texas 77030, USA.
Clin Cancer Res. 2010 Feb 15;16(4):1179-90. doi: 10.1158/1078-0432.CCR-09-1787. Epub 2010 Feb 9.
Low-molecular-weight cyclin E (LMW-E) in breast cancer cells induces genomic instability and resistance to inhibition by p21, p27, and fulvestrant therapy. Here, we sought to determine if LMW-E renders breast cancer cells unresponsive to aromatase inhibitors (AI), elucidate the mechanism of such resistance, and ascertain if inhibitors of LMW-E-associated kinase activity could overcome this resistance.
The antiproliferative effects of the AIs were examined in aromatase-overexpressing MCF-7/Ac1 cells in the presence or absence of full-length cyclin E and LMW-E. Inhibition of LMW cyclin E kinase activity by roscovitine [a cyclin-dependent kinase (CDK) inhibitor] was examined in letrozole-unresponsive MCF-7/Ac1 cells. The role of LMW-E and CDK2 in mediating recurrence following AI treatment was also assessed in breast cancer patients.
Overexpression of LMW-E in postmenopausal patients was associated with a poor prognosis. Letrozole, but not exemestane or anastrozole, mediated a pronounced G(1) arrest in MCF-7/Ac1 cells. Androstenedione-induced G(1) exit correlated with increased cyclin E-associated kinase activity and increased CDK2 levels. Letrozole treatment inhibited cyclin E-CDK2 kinase activity by preventing the androstenedione-induced increase in CDK2. LMW-E bypassed this effect and rendered the cells resistant to letrozole inhibition. Roscovitine blocked the androstenedione-induced increase in CDK2, and LMW-E overexpression could not bypass this effect. Lastly, breast cancer patients whose tumors overexpress LMW-E were not responsive to AI treatment.
Roscovitine treatment can reverse intrinsic or acquired resistance to letrozole due to LMW-E expression in breast cancer cells. These data support the clinical investigation of CDK2 inhibitor therapy for postmenopausal women with estrogen receptor-positive, LMW-E-expressing breast cancer.
乳腺癌细胞中的低分子量细胞周期蛋白 E（LMW-E）可诱导基因组不稳定性，并对 p21、p27 和氟维司群治疗产生耐药性。在此，我们试图确定 LMW-E 是否使乳腺癌细胞对芳香酶抑制剂（AI）无反应，阐明这种耐药性的机制，并确定 LMW-E 相关激酶活性的抑制剂是否可以克服这种耐药性。
在存在全长细胞周期蛋白 E 和 LMW-E 的情况下，检测芳香酶过表达 MCF-7/Ac1 细胞中 AI 的增殖抑制作用。用罗昔司特[一种细胞周期依赖性激酶（CDK）抑制剂]抑制 LMW 细胞周期蛋白 E 激酶活性，检测其在来曲唑无反应的 MCF-7/Ac1 细胞中的作用。还评估了 LMW-E 和 CDK2 在介导 AI 治疗后复发中的作用在乳腺癌患者中。
绝经后患者中 LMW-E 的过表达与预后不良相关。来曲唑而非依西美坦或阿那曲唑可使 MCF-7/Ac1 细胞明显 G1 期阻滞。雄烯二酮诱导的 G1 期退出与细胞周期蛋白 E 相关激酶活性增加和 CDK2 水平增加相关。来曲唑通过防止雄烯二酮诱导的 CDK2 增加来抑制细胞周期蛋白 E-CDK2 激酶活性。LMW-E 绕过了这种作用，使细胞对来曲唑的抑制产生耐药性。罗昔司特阻断了雄烯二酮诱导的 CDK2 增加，而 LMW-E 的过表达不能绕过这种作用。最后，肿瘤过度表达 LMW-E 的乳腺癌患者对 AI 治疗无反应。
罗昔司特治疗可逆转由于乳腺癌细胞中 LMW-E 表达而导致的来曲唑固有或获得性耐药。这些数据支持对雌激素受体阳性、LMW-E 表达的绝经后乳腺癌患者进行 CDK2 抑制剂治疗的临床研究。
