Introduction: Pregnant women with breast cancer present with a more advanced disease compared to non-pregnant women. Nevertheless, breast cancer metastasis to placenta is rare. Extravillous-trophoblast (EVT) cells /tumor implantations share the same biochemical mediators, while only the first is stringently controlled. We hypothesized that mechanisms which affect/ restrain trophoblast implantation may inhibit placental metastasis. The objective of the study was to analyze the effects of placenta on breast cancer cells.
Materials: First trimester human placental explants were cocultured with MCF7-GFP cells on matrigel. Following culture, wells were either immunohistochemicaly analysed (IHC) or MCF7 cells were sorted by their GFP expression for further analysis. The tested parameters were: proliferation (IHC), cell-cycle (FACS), apoptosis (IHC, FACS), cell count (Sorter), cells distribution around the placenta (visual observation), cells invasion (Transwell), MMPs activity (Zymogram) and estrogen receptor expression (ER, Immunoblot, IHC). Microarray analysis was done on MCF7 cultured with\without the placenta.
Results: Reduced MCF7 cell number (~50%↓, P<0.05) was observed near EVT cells. The placenta did not affect MCF7 cell-cycle and only modestly elevated their apoptotic rate (17%↑, P<0.05). Our findings suggest breast cancer cell migration/detachment from EVT cells area since: 1. MCF-7 cells formed elongated aggregates which eventually disappeared, process accompanied by elevated MMP2 that facilitate invasion. 3. Placental soluble factors significantly affected MCF7 cell invasion. 4. The placenta reduced MCF7 cells ER expression which is character of motile cells. Microarray results demonstrated significant changes in genes related to cell adhesion, glycan, breast carcinoma estrogen, JAK-STAT and developmental pathways.
Conclusions: Our study demonstrates that MCF7 cells are eliminated from the EVT cells surroundings, suggesting it as a non-supporting microenvironment for breast cancer cells. The molecular pathways responsible for the changed MCF7 phenotype are now being explored and may have future therapeutic implications.
1,3,4,5. Oncogenetic laboratory, Department of Medicine ‘A,, Department of Obstetrics & Gynecology, Hematological Laboratory, Meir Medical Center, Kfar-Saba, Israel. 2. Sackler Faculty of Medicine, Tel Aviv University
Tartakover-Matalon S1,2, Mizrahi A1,2, Epstein G1,2, Shneifi A1,3, Drucker L1,2 Pomeranz M1,2,4, Fishman A1,2,4, Radnay J5, Lishner M1,2,3