Epstein Shochet Gali, Tartakover-Matalon Shelly, Drucker Liat, Pasmanik-Chor Metsada, Pomeranz Meir, Fishman Ami, Lishner Michael
Oncogenetic Laboratory, Meir Medical Center, 45 Tschernchovski St., Kfar Saba, 44281, Israel.
Clin Exp Metastasis. 2014 Dec;31(8):961-75. doi: 10.1007/s10585-014-9683-0. Epub 2014 Oct 15.
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.
与未怀孕女性相比，被诊断为妊娠相关乳腺癌的女性通常患有晚期癌症并伴有转移，且雌激素受体α（ERα）表达降低。然而，转移至胎盘的情况并不常见。此前，我们证明了乳腺癌细胞（MCF-7/T47D）可从体外人胎盘外植体植入部位迁移。我们旨在分析胎盘植入过程中产生的因素或植入胎盘与癌细胞相互作用的结果对癌细胞迁移和侵袭性的影响。我们收集了植入胎盘和胎盘-乳腺癌细胞共培养物的上清液，并分析了它们对癌细胞表型和信号通路的影响。从乳腺癌细胞收集的上清液用作对照。我们发现，从植入胎盘收集的上清液可诱导适度的癌细胞迁移，但不伴有上皮-间质转化（EMT），可支持乳腺癌细胞存活并增加MCF-7细胞数量。共培养上清液可诱导MCF-7细胞过度运动和EMT。这种EMT由Smad3和JNK/ERK激活介导。胎盘和共培养上清液均降低了癌细胞中ERα的表达。最后，我们表明，与人类胎盘外植体共培养的MCF-7经历了JNK和Smad3信号通路的持续激活以及EMT过程，这导致它们从胎盘植入部位迁移。这些发现可能解释了孕期乳腺癌中ERα降低和转移增加的现象，并突出了其中涉及的信号通路。
