title: Cyclooxygenase-2 regulates TGFβ-induced cancer stemness in triple-negative breast cancer.
abstract: Triple negative breast cancer (TNBC), an aggressive subtype of breast cancer, display poor prognosis and exhibit resistance to conventional therapies, partly due to an enrichment in breast cancer stem cells (BCSCs). Here, we investigated the role of the cyclooxygenase-2 (COX-2), a downstream target of TGFβ, in regulating BCSCs in TNBC. Bioinformatics analysis revealed that COX-2 is highly expressed in TNBC and that its expression correlated with poor survival outcome in basal subtype of breast cancer. We also found TGFβ-mediated COX-2 expression to be Smad3-dependent and to be required for BCSC self-renewal and expansion in TNBCs. Knocking down COX-2 expression strikingly blocked TGFβ-induced tumorsphere formation and TGFβ-induced enrichment of the two stem-like cell populations, CD24lowCD44highand ALDH+ BCSCs. Blocking COX-2 activity, using a pharmacological inhibitor also prevented TGFβ-induced BCSC self-renewal. Moreover, we found COX-2 to be required for TGFβ-induced expression of mesenchymal and basal breast cancer markers. In particular, we found that TGFβ-induced expression of fibronectin plays a central role in TGFβ-mediated breast cancer stemness. Together, our results describe a novel role for COX-2 in mediating the TGFβ effects on BCSC properties and imply that targeting the COX-2 pathway may prove useful for the treatment of TNBC by eliminating BCSCs.
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: Mahmood Y
authors.initials: MY
authors.lastname: Hachim
authors.affiliation: Department of Medicine, McGill University Health Center, Cancer Research Program, Montreal, Quebec, H4A 3J1, Canada.
authors.forename: Ibrahim Y
authors.initials: IY
authors.lastname: Hachim
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: 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: Fatmah Al
authors.initials: FA
authors.lastname: Raffa
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 / Q000378:metabolism; D051927:CD24 Antigen / Q000378:metabolism; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D051900:Smad3 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D051927:CD24 Antigen; C497889:CD24 protein, human; C497483:CD44 protein, human; D005353:Fibronectins; D018960:Hyaluronan Receptors; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human