Targeting low molecular weight cyclin E (LMW-E) in breast cancer

• Published in: Breast cancer research and treatment Vol. 132; no. 2; pp. 575 - 588
• Main Authors: Nanos-Webb, Angela, Jabbour, Natalie A., Multani, Asha S., Wingate, Hannah, Oumata, Nassima, Galons, Hervé, Joseph, Benoît, Meijer, Laurent, Hunt, Kelly K., Keyomarsi, Khandan
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.04.2012; Springer; Springer Nature B.V; Springer Verlag
• Subjects: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Biological and medical sciences; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer; Cancer research; Cancer therapies; Cell death; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chemical Sciences; Chemotherapy; Chromosome Aberrations; Cyclin E; Cyclin E - genetics; Cyclin E - metabolism; Cyclin-dependent kinase; Cyclin-dependent kinase 2; Cyclin-Dependent Kinase 2 - antagonists & inhibitors; Cyclin-Dependent Kinase 2 - metabolism; Dose-Response Relationship, Drug; Doxorubicin; Doxorubicin - pharmacology; Drug Synergism; Drug therapy; Enzyme Induction; Female; Gene expression; Genomic instability; Genomic Instability - drug effects; Gynecology. Andrology. Obstetrics; Humans; Mammary gland diseases; Medical sciences; Medicine; Medicine & Public Health; Molecular Weight; Oncology; Organic chemistry; Polyploidy; Preclinical Study; Prognosis; Protein Kinase Inhibitors - pharmacology; Purines - pharmacology; roscovitine; Time Factors; Transfection; Transgenes; Tumorigenesis; Tumors; LMW cyclin E; Roscovitine; CDK inhibitors; Seliciclib; CYC202; Doxorubicin; Antineoplastic agent; DNA topoisomerase (ATP-hydrolysing); Purine derivatives; Breast disease; Targeting; Enzyme; Enzyme inhibitor; Breast cancer; Topoisomerase II inhibitor; Malignant tumor; Low molecular weight; Cyclin dependent kinase inhibitor; Mammary gland diseases; Target; Isomerases; Anthracyclins; Cyclin E; Cancer
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-011-1638-4

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.