title: P-cadherin functional role is dependent on E-cadherin cellular context: a proof of concept using the breast cancer model.
abstract: P-cadherin overexpression is associated with worse breast cancer survival, being a poor prognostic marker as well as a putative therapeutic target for the aggressive triple-negative and basal-like carcinomas (TNBCs). Previously, we have shown that P-cadherin promotes breast cancer invasion of cells where membrane E-cadherin was maintained; however, it suppresses invasion in models without endogenous cadherins, like melanomas. Here, we investigated if P-cadherin expression would interfere with the normal adhesion complex and which were the cellular/molecular consequences, constituting, in this way, a new mechanism by which E-cadherin invasive-suppressor function was disrupted. Using breast TNBC models, we demonstrated, for the first time, that P-cadherin co-localizes with E-cadherin, promoting cell invasion due to the disruption caused in the interaction between E-cadherin and cytoplasmic catenins. P-cadherin also induces cell migration and survival, modifying the expression profile of cells expressing wild-type E-cadherin and contributing to alter their cellular behaviour. Additionally, E- and P-cadherin co-expressing cells significantly enhanced in vivo tumour growth, compared with cells expressing only E- or only P-cadherin. Finally, we still found that co-expression of both molecules was significantly correlated with high-grade breast carcinomas, biologically aggressive, and with poor patient survival, being a strong prognostic factor in this disease. Our results show a role for E- and P-cadherin co-expression in breast cancer progression and highlight the potential benefit of targeting P-cadherin in the aggressive tumours expressing high levels of this protein.
authors.affiliation: IPATIMUP, Institute of Molecular Pathology and Immunology of the University of Porto, Rua Dr Roberto Frias s/n, Porto, Portugal.
authors.forename: Ana Sofia
authors.initials: AS
authors.lastname: Ribeiro
authors.forename: Bárbara
authors.initials: B
authors.lastname: Sousa
authors.forename: Laura
authors.initials: L
authors.lastname: Carreto
authors.forename: Nuno
authors.initials: N
authors.lastname: Mendes
authors.forename: Ana Rita
authors.initials: AR
authors.lastname: Nobre
authors.forename: Sara
authors.initials: S
authors.lastname: Ricardo
authors.forename: André
authors.initials: A
authors.lastname: Albergaria
authors.forename: Jorge F
authors.initials: JF
authors.lastname: Cameselle-Teijeiro
authors.forename: Rene
authors.initials: R
authors.lastname: Gerhard
authors.forename: Ola
authors.initials: O
authors.lastname: Söderberg
authors.forename: Raquel
authors.initials: R
authors.lastname: Seruca
authors.forename: Manuel A
authors.initials: MA
authors.lastname: Santos
authors.forename: Fernando
authors.initials: F
authors.lastname: Schmitt
authors.forename: Joana
authors.initials: J
authors.lastname: Paredes
mesh_terms: D000818:Animals; D015703:Antigens, CD; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D002470:Cell Survival; D018572:Disease-Free Survival; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D011379:Prognosis; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; C512197:CDH3 protein, human; D015820:Cadherins; D012333:RNA, Messenger