title: Targeting low molecular weight cyclin E (LMW-E) in breast cancer.
abstract: 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.
authors.affiliation: Department of Experimental Radiation Oncology, M D Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Nanos-Webb
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Jabbour
authors.forename: Asha S
authors.initials: AS
authors.lastname: Multani
authors.forename: Hannah
authors.initials: H
authors.lastname: Wingate
authors.forename: Nassima
authors.initials: N
authors.lastname: Oumata
authors.forename: Hervé
authors.initials: H
authors.lastname: Galons
authors.forename: Benoît
authors.initials: B
authors.lastname: Joseph
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
authors.forename: Kelly K
authors.initials: KK
authors.lastname: Hunt
authors.forename: Khandan
authors.initials: K
authors.lastname: Keyomarsi
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D002869:Chromosome Aberrations; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D004357:Drug Synergism; D004790:Enzyme Induction; D005260:Female; D042822:Genomic Instability / Q000187:drug effects; D006801:Humans; D008970:Molecular Weight; D011123:Polyploidy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D000077546:Roscovitine; D013997:Time Factors; D014162:Transfection
chemical_list: D019927:Cyclin E; D047428:Protein Kinase Inhibitors; D011687:Purines; D000077546:Roscovitine; D004317:Doxorubicin; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2