title: First trimester human placenta prevents breast cancer cell attachment to the matrix: The role of extracellular matrix.
abstract: The extracellular matrix (ECM) affects cancer cell characteristics. Its detachment from the ECM induces cell apoptosis, termed anoikis. Cancer cells can develop anoikis resistance, a necessary step for metastasis, by switching integrins, over-expressing growth factor receptors, and inducing epithelial mesenchymal transition (EMT). The placenta is a non-supportive microenvironment for cancer cells. We showed that breast cancer cells (BCCL) were eliminated from placental implantation sites. During implantation, the placenta manipulates its surrounding matrix, which may induce BCCL elimination. Here, we explored the effect of placenta-induced ECM manipulations on BCCL. During experiments, BCCL (MCF-7/T47D) were cultured on placenta/BCCL-conditioned ECM (Matrigel used for first trimester placenta/BCCL culture and cleared by NH4OH). After culturing the cells, we analyzed cancer cell phenotype (death, count, aggregation, MMP) and signaling (microarray analysis and pathway validation). We found that the BCCL did not attach to previous placental implantation sites and instead, similarly to anoikis-resistant cells, migrated away, displayed increased MMP levels/activity, and formed aggregates in distant areas. T47D were less affected than the MCF-7 cells, since MCF-7 also showed modest increases in cell death, EMT, and increased proliferation. Microarray analysis of the MCF-7 highlighted changes in the integrin, estrogen, EGFR, and TGFβ pathways. Indeed, placental ECM reduced ERα, induced Smad3/JNK phosphorylation and increased integrin-α5 expression (RGD-dependent integrin) in the BCCL. Addition of RGD or TGFβR/JNK inhibitors reversed the phenotypic changes. This study helps explain the absence of metastases to the placenta and why advanced cancer is found in pregnancy, and provides possible therapeutic targets for anoikis-resistant cells. © 2016 Wiley Periodicals, Inc.
authors: Oncogenetic Laboratory, Meir Medical Center, Kfar Saba, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors: Gali
authors: G
authors: Epstein Shochet
authors: Oncogenetic Laboratory, Meir Medical Center, Kfar Saba, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors: Liat
authors: L
authors: Drucker
authors: Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Department of Obstetrics and Gynecology, Meir Medical Center, Kfar Saba, Israel.
authors: Meir
authors: M
authors: Pomeranz
authors: Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Department of Obstetrics and Gynecology, Meir Medical Center, Kfar Saba, Israel.
authors: Ami
authors: A
authors: Fishman
authors: Bioinformatics Unit, Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
authors: Metsada
authors: M
authors: Pasmanik-Chor
authors: Oncogenetic Laboratory, Meir Medical Center, Kfar Saba, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors: Shelly
authors: S
authors: Tartakover-Matalon
authors: Oncogenetic Laboratory, Meir Medical Center, Kfar Saba, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Department of Internal Medicine A, Meir Medical Center, Kfar Saba, Israel.
authors: Michael
authors: M
authors: Lishner
mesh_terms: D023102:Anoikis; D001943:Breast Neoplasms / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D006801:Humans; D039503:Integrin alpha6 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D061986:MCF-7 Cells; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic / Q000378:metabolism; D011261:Pregnancy Trimester, First; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C588002:ITGA6 protein, human; D039503:Integrin alpha6; D016212:Transforming Growth Factor beta
keywords: ECM; TGFβ/JNK; breast cancer; integrin; placenta