title: CDK4 regulates cancer stemness and is a novel therapeutic target for triple-negative breast cancer.
abstract: Triple negative breast cancers exhibit very aggressive features and poor patient outcomes. These tumors are enriched in cancer stem cells and exhibit resistance to most treatments and chemotherapy. In this study, we found the cyclin-dependent kinase (CDK4) to act as a cancer stem cell regulator and novel prognostic marker in triple negative breast cancers. We found CDK4 to be highly expressed in these tumors and its expression to correlate with poor overall and relapse free survival outcomes, high tumor grade and poor prognostic features of triple negative breast cancer patients. Moreover, we found that blocking CDK4 expression or kinase activity, using a pharmacological inhibitor prevented breast cancer stem cell self-renewal. Interestingly, suppression of CDK4 expression or kinase activity reversed the basal-B TNBC mesenchymal phenotype to an epithelial- and luminal-like phenotype which correlates with better clinical prognosis. Finally, blocking CDK4 activity efficiently eliminated both normal and chemotherapy-resistant cancer cells in triple negative breast cancers, highlighting CDK4 as a promising novel therapeutic target for these aggressive breast tumors.
authors.affiliation: Department of Medicine, McGill University Health Center, Cancer Research Program, Montreal, Quebec, H4A 3J1, Canada.
authors.forename: Meiou
authors.initials: M
authors.lastname: Dai
authors.affiliation: Department of Medicine, McGill University Health Center, Cancer Research Program, Montreal, Quebec, H4A 3J1, Canada.
authors.forename: Chenjing
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Medicine, McGill University Health Center, Cancer Research Program, Montreal, Quebec, H4A 3J1, Canada.
authors.forename: Ayad
authors.initials: A
authors.lastname: Ali
authors.affiliation: Department of Medicine, McGill University Health Center, Cancer Research Program, Montreal, Quebec, H4A 3J1, Canada.
authors.forename: Xinyuan
authors.initials: X
authors.lastname: Hong
authors.affiliation: Department of Medicine, McGill University Health Center, Cancer Research Program, Montreal, Quebec, H4A 3J1, Canada.
authors.forename: Jun
authors.initials: J
authors.lastname: Tian
authors.affiliation: Department of Medicine, McGill University Health Center, Cancer Research Program, Montreal, Quebec, H4A 3J1, Canada.
authors.forename: Chieh
authors.initials: C
authors.lastname: Lo
authors.affiliation: Department of Medicine, McGill University Health Center, Cancer Research Program, Montreal, Quebec, H4A 3J1, Canada.
authors.forename: Nadège
authors.initials: N
authors.lastname: Fils-Aimé
authors.affiliation: Department of Animal Science, McGill University, Sainte-Anne-de-Bellevue, H9X 3V9, Canada.
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Burgos
authors.affiliation: Department of Medicine, McGill University Health Center, Cancer Research Program, Montreal, Quebec, H4A 3J1, Canada.
authors.forename: Suhad
authors.initials: S
authors.lastname: Ali
authors.affiliation: Department of Medicine, McGill University Health Center, Cancer Research Program, Montreal, Quebec, H4A 3J1, Canada.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Lebrun
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D045744:Cell Line, Tumor; D000066673:Cell Self Renewal / Q000235:genetics; D051358:Cyclin-Dependent Kinase 4 / Q000008:administration & dosage / Q000235:genetics*; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D058990:Molecular Targeted Therapy; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4