title: Placenta-breast cancer cell interactions promote cancer cell epithelial mesenchymal transition via TGFβ/JNK pathway.
abstract: Women diagnosed with pregnancy associated breast cancer often have advanced cancer with metastases and reduced expression of ERα compared to non-pregnant women. Nevertheless, metastases to the placenta are uncommon. Previously, we demonstrated that breast cancer cells (MCF-7/T47D) migrated from ex vivo human placental explant implantation sites. We aimed to analyze the effect of factors produced during placental implantation or as a result of the interaction between the implanted placentae to cancer cells on cancer cells migration and aggressiveness. We collected supernatants from implanted placentae and placental-breast cancer cells cocultures and analyzed their effects on cancer cells phenotype and pathways. Supernatants collected from breast cancer cells served as controls. We found that supernatants collected from implanted placentae induced modest cancer cells migration that was not accompanied by epithelial to mesenchymal transition (EMT), supported breast cancer cells survival and elevated MCF-7 cell number. The coculture supernatant induced excessive motility and EMT of the MCF-7 cells. This EMT was mediated by Smad3 and JNK/ERK activation. Both placenta and coculture supernatants reduced ERα expression in the cancer cells. Finally, we showed that MCF-7 cocultured with the human placental explants underwent continuous activation of JNK and Smad3 pathways and the EMT process, which led to their migration away from the placental implantation sites. These findings may explain the reduced ERα and elevated metastases found in breast cancer during pregnancy and highlights pathways involved in it.
authors.affiliation: Oncogenetic Laboratory, Meir Medical Center, 45 Tschernchovski St., Kfar Saba, 44281, Israel.
authors.forename: Gali
authors.initials: G
authors.lastname: Epstein Shochet
authors.forename: Shelly
authors.initials: S
authors.lastname: Tartakover-Matalon
authors.forename: Liat
authors.initials: L
authors.lastname: Drucker
authors.forename: Metsada
authors.initials: M
authors.lastname: Pasmanik-Chor
authors.forename: Meir
authors.initials: M
authors.lastname: Pomeranz
authors.forename: Ami
authors.initials: A
authors.lastname: Fishman
authors.forename: Michael
authors.initials: M
authors.lastname: Lishner
mesh_terms: D017209:Apoptosis; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D002450:Cell Communication; D002453:Cell Cycle; D002465:Cell Movement; D049109:Cell Proliferation; D018920:Coculture Techniques; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D010920:Placenta / Q000378:metabolism / Q000473:pathology*; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment
chemical_list: D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D048031:JNK Mitogen-Activated Protein Kinases