Coppola, Luigi (2017) Targeting subtypes of breast cancer with Palbociclib, a cyclin-dependent Kinase inhibitor. [Tesi di dottorato]

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Abstract

Background: Breast cancer is the leading cause of cancer death in women. Despite major advances in breast cancer research, the recurrence of cancer represents a serious obstacle to successful treatment; deregulation in cell cycle proteins have been implicated in different cancers including breast. A pharmacological approach to inhibit cyclin - dependent kinases 4 and 6 (CDK 4/6) using Palbociclib, a highly selective small molecule inhibitor, was used to evaluate the effects of this inhibitor on cell proliferation of 4 different breast cancer cells subtypes (MCF-7, MDA-MB-231,BT474Z, MCF-7/her2 transfected). Methods: ERα and Cyclin D1 expression has been evaluated on 34 breast cancer specimens; 4 human immortalized breast cancer cell lines (BT474Z, MCF-7, MCF7/her2 transfected, MDA-MB-231) and one cell line derived from breast cancer tissue patient (K90) have been treated with increasing concentrations of Palbociclib (cyclin D1-CDK4/6 inhibitor); cell proliferation was evaluate by MTT assay and cell count. Cell cycle analysis and protein expression have been performed by Facs and WB. Results: ERα-positive MCF-7 cells are more sensitive to Palbociclib compared to the other breast cancer cell subtypes; Palbociclib displays a cytostatic effect by inhibiting cell viability and proliferation; the inhibitory effect of Palbociclib is based on breast cancer cells subtypes through modulation of expression of G0/G1 regulators (cyclin D1, p27, Rb and phospo-Rb). Conclusion: This study suggests a potential role of CDK 4/6 inhibitor Palbociclib on different breast cancer subtypes and identifies Luminal A and Luminal B breast cancer as possible target of Palbociclib in clinical setting.

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