Oncogenetic Laboratory, Meir Medical Center, 45 Tschernchovski St, Kfar Saba 44281, Israel.
Hum Reprod. 2012 Jan;27(1):73-88. doi: 10.1093/humrep/der365. Epub 2011 Nov 2.
Breast cancer during pregnancy is often more advanced than in non-pregnant women. Nevertheless, no case of metastasis inside the placenta has been reported. Previously, we showed that placental-explants eliminated breast cancer cells from their surroundings, due to cell-death and elevated migration. Our objective was to find the underlying mechanisms of these phenomena.
Our model contained Michigan Cancer Foundation 7 (MCF7) or T47D cells co-cultured with and without human placental explants. Microarray analysis, validated by quantitative PCR, of MCF7 following their placental co-culture suggested activation of estrogen (E(2)) signaling. As extensive cross-talk exists between E(2) and progesterone, their involvement in mediating placental effects on breast cancer cells was tested. Indeed, addition of E(2) and progesterone receptor (ER and PR) inhibitors to the co-culture system reduced cancer cell motility, yet did not alter cell-cycle or death. E(2) and progesterone concentrations in placental media were found to be similar to those of early pregnancy blood levels. Interestingly, placental-breast cancer co-culture media contained lower progesterone (P < 0.05) and higher E(2) (200%, P < 0.05) levels than placentae cultured separately. Placental supernatant and E(2) and progesterone at placental levels were sufficient to increase MCF7 and T47D migration and invasion (P < 0.05), yet did not alter MCF7 cell-cycle or death. Furthermore, placental supernatant elevated p38 and Jun N-terminal kinase (JNK) phosphorylation in both cell lines (P < 0.05). Inhibitors of JNK, ER and PR reversed MCF7 and T47D motility induced by the placenta, suggesting their involvement.
We suggest that E(2) and progesterone contribute to cell migration away from placental areas. We hypothesize that they may increase metastatic spread to other organs in pregnancy.
怀孕期间的乳腺癌通常比非妊娠妇女更为晚期。然而，尚未有报道称胎盘内转移。先前，我们表明胎盘外植体能通过细胞死亡和迁移增加来消除周围的乳腺癌细胞。我们的目标是找到这些现象的潜在机制。
我们的模型包含密歇根癌症基金会 7 号（MCF7）或 T47D 细胞与胎盘外植体共培养和不共培养。共培养后 MCF7 的微阵列分析通过定量 PCR 验证表明雌激素（E2）信号转导被激活。由于 E2 和孕激素之间存在广泛的交叉对话，因此测试了它们在介导胎盘对乳腺癌细胞的影响中的作用。实际上，向共培养系统中添加 E2 和孕激素受体（ER 和 PR）抑制剂可降低癌细胞的迁移能力，但不会改变细胞周期或死亡。发现胎盘培养基中的 E2 和孕激素浓度与妊娠早期的血液水平相似。有趣的是，胎盘-乳腺癌共培养培养基中的孕激素水平（P <0.05）低于胎盘单独培养的孕激素水平（P <0.05），而 E2 水平（200％，P <0.05）则高于胎盘单独培养的 E2 水平。胎盘上清液和胎盘水平的 E2 和孕激素足以增加 MCF7 和 T47D 的迁移和侵袭（P <0.05），但不会改变 MCF7 的细胞周期或死亡。此外，胎盘上清液增加了两条细胞系中的 p38 和 Jun N-末端激酶（JNK）磷酸化（P <0.05）。JNK、ER 和 PR 抑制剂逆转了胎盘诱导的 MCF7 和 T47D 运动，表明它们的参与。
我们认为 E2 和孕激素有助于细胞从胎盘区域迁移。我们假设它们可能会增加怀孕期间向其他器官的转移扩散。
