Low-Molecular-Weight Cyclin E Can Bypass Letrozole-Induced G1 Arrest in Human Breast Cancer Cells and Tumors

Purpose: 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. Experimental Design: 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. Results: Overexpression of LMW-E in postmenopausal patients was ssociated 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. Conclusions: 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. Clin Cancer Res; 16(4); 1179-90. (C) 2010 AACR.