title: Combinatorial PX-866 and Raloxifene Decrease Rb Phosphorylation, Cyclin E2 Transcription, and Proliferation of MCF-7 Breast Cancer Cells.
abstract: As a potential means to reduce proliferation of breast cancer cells, a multiple-pathway approach with no effect on control cells was explored. The human interactome being constructed by the Center for Cancer Systems Biology will prove indispensable to understanding composite effects of multiple pathways, but its discovered protein-protein interactions require characterization. Accordingly, we explored the effects of regulators of one protein on downstream targets of the other protein. MCF-7 estrogen receptor-positive (ER+) breast cancer cells were treated with raloxifene to upregulate the TGF-β pathway and PX-866 to down-regulate the PI3K/Akt pathway. This resulted in highly significant downstream reduction of cell cycle proliferation in breast cancer cells with no significant proliferation reduction following similar treatment of noncancerous MCF10A breast epithelial cells. Reduced phosphorylation of p107 and substantial reduction of Rb phosphorylation were observed in response. The effects of reduced Rb and p107 phosphorylation were reflected in significant decline in E2F-1 transcriptional activity, which is dependent on pocket protein phosphorylation status. The reduced proliferation was related to decreased expression of cyclins, including E2F-1-regulated Cyclin E2, which was also in response to raloxifene and PX-866. All combinations of raloxifene and PX-866 produced significant or highly significant results for reduced MCF-7 cell proliferation, reduced Cyclin E2 transcription, and reduced Rb phosphorylation. These studies demonstrated that uncontrolled proliferation of ER+ breast cancer cells can be significantly reduced by combinational targeting of two relevant pathways. J. Cell. Biochem. 117: 1688-1696, 2016. © 2015 Wiley Periodicals, Inc.
authors.affiliation: Department of Biology, University of Alabama, Birmingham, Alabama.
authors.forename: Gregory W
authors.initials: GW
authors.lastname: Peek
authors.affiliation: Department of Biology, University of Alabama, Birmingham, Alabama.|Comprehensive Cancer Center, University of Alabama, Birmingham, Alabama.|Comprehensive Center for Healthy Aging, University of Alabama, Birmingham, Alabama.|Comprehensive Diabetes Center, University of Alabama, Birmingham, Alabama.|Nutrition Obesity Research Center, University of Alabama, Birmingham, Alabama.
authors.forename: Trygve O
authors.initials: TO
authors.lastname: Tollefsbol
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D016213:Cyclins / Q000096:biosynthesis*; D050687:E2F1 Transcription Factor / Q000378:metabolism; D005260:Female; D006067:Gonanes / Q000494:pharmacology*; D006801:Humans; D061986:MCF-7 Cells; D020849:Raloxifene Hydrochloride / Q000494:pharmacology*; D016160:Retinoblastoma Protein / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: C503688:CCNE2 protein, human; D016213:Cyclins; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D006067:Gonanes; C496788:PX-866; D016160:Retinoblastoma Protein; D020849:Raloxifene Hydrochloride
keywords: BREAST CANCER; PI3K/Akt PATHWAY; POCKET PROTEIN; PROLIFERATION; PX-866; RALOXIFENE; Rb PHOSPHORYLATION; TGF-β PATHWAY; p107