Abstract P5-05-05: Low molecular weight cyclin E regulates response to aromatase inhibitors in post-menopausal breast cancer patients

Abstract

Abstract Almost seventy percent of all breast cancer patients have estrogen receptor (ER) positive tumors requiring hormonal therapy. Aromatase inhibitors (AIs) are considered as the first line hormonal therapy for ER+ post-menopausal patients. However, resistance to these drugs remains a major challenge in clinic and the biology of such resistance is not clear. Previous studies have shown that cyclin E pathway, a key regulator in the G1 to S transition of cell cycle, is deregulated in breast cancer. Full-length cyclin E is abnormally cleaved into low molecular weight isoforms (LMW-E) that renders patients to poor survival. Here we hypothesize that cyclin E deregulation can confer resistance to AIs. To address this, we engineered aromatase overexpressing MCF7 cells to overexpress LMW-E under doxycycline inducible promoter. Full-length cyclin E, GFP and empty vector transfected cells were also generated and used as controls. Our results indicated that AIs inhibited proliferation by arresting the cells at G1 phase of the cell cycle. However, LMW-E expression significantly enhanced proliferation of the cells when treated with AIs. In addition, LMW-E bypassed G1 arrest following AI treatment. At the molecular level, AIs decreased CDK2, pCDK2, and Rb levels and attenuated Rb phosphorylation. However, these effects were completely rescued only when LMW-E was expressed. Moreover, using an in vitro kinase assay we indicated that AIs decreased CDK2 kinase activity while LMW-E expression reversed this effect by increasing CDK2 enzymatic activity. Taken together, these results suggest that LMW-E inactivates Rb protein as a tumor suppressor and renders the cells to bypass G1 checkpoint following AI treatment. In addition, this study provides early evidence that CDK2 inhibitors could be beneficial in combination with AIs for LMW-E expressing tumors. Currently we are investigating whether LMW-E can bypass the activity of AIs using inducible breast cancer cell line xenograft. We are also examining the correlation between cyclin E status and response to treatment in a cohort of patients who received AIs in the neo-adjuvant setting. Citation Format: Iman Doostan, Stacy L Moulder, Kelly K Hunt, Khandan Keyomarsi. Low molecular weight cyclin E regulates response to aromatase inhibitors in post-menopausal breast cancer patients [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-05-05.