Targeting low molecular weight cyclin E (LMW-E) in breast cancer
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Low molecular weight cyclin E (LMW-E) plays an important oncogenic role in breast cancer. LMW-E, which is not found in normal tissue, can promote the formation of aggressive tumors and can lead to increased genomic instability and tumorigenesis. Additionally, breast cancer patients whose tumors express LMW-E have a very poor prognosis. Therefore, we investigated LMW-E as a potential specific target for treatment either alone or in combination therapy. We hypothesized that because LMW-E binds to CDK2 more efficiently than full length cyclin E, resulting in increased activity, CDK inhibitors could be used to target tumors with LMW-E bound to CDK2. To test the hypothesis, an inducible full length and LMW-E MCF7-Tet-On system was established. Cyclin E (full length (EL) or LMW-E) is only expressed upon induction of the transgene. The doubling times of cells were unchanged when the transgenes were induced. However, upon induction, the kinase activity associated with LMW-E was much higher than that in the EL induced cells or any of the uninduced cells. Additionally only the LMW-E induced cells underwent chromosome aberrations and increased polyploidy. By examining changes in proliferation and survival in cells with induced full length and LMW-E, CDK inhibitors alone were determined to be insufficient to specifically inhibit LMW-E expressing cells. However, in combination with Doxorubicin, the CDK inhibitor, Roscovitine (Seliciclib, CYC202), synergistically led to increased cell death in LMW-E expressing cells. Clinically, the combination of CDK inhibitors and chemotherapy such as Doxorubicin provides a viable personalized treatment strategy for those breast cancer patients whose tumors express the LMW-E.
KeywordsRoscovitine Seliciclib CYC202 Doxorubicin LMW cyclin E CDK inhibitors
We would like to thank Tuyen Bui for his assistance on the generation of the MCF7-Tet-On T2 cell line. Also, we would like to thank Yanna Liu for the immunofluorescence of the MCF7-Tet-On cells. We would also like to thank Jin Ma for the time spent preparing the MCF7-Tet-On samples for metaphase spread analysis. This research was supported by NIH grants CA87458, P50CA116199, Susan G. Komen grants KG100521 and KG100876 to Khandan Keyomarsi and Kelly K. Hunt, by the CCTS T32 grant to Natalie Jabbour through the NIH Clinical and Translational Award TL1 RR024147, by NCI CCSG grant CA16672 to M.D. Anderson Cancer Center, “Cancéropole Grand-Ouest”, the “Association pour la Recherche sur le Cancer” (ARC-1092), the “Ligue Nationale contre le Cancer (Comité Grand-Ouest)” to Laurent Meijer.
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