Abstract
Purpose
Pregnancy-associated breast cancer (PABC) is usually diagnosed at an advanced stage in comparison to non-pregnant women. The placenta secretes hormones and cytokines, which affect breast cancer progression. Previously, we demonstrated that human placental secretome facilitates the survival and migration of ERα+ breast cancer cells (BCCL), but pregnant women have a relatively high frequency of ERα-negative tumors. In the current study, we analyzed the effect of placental secretome on ERα-negative BCCL.
Methods
BCCL [MCF-7(estrogen/progesterone receptor positive (ERα+/PR+), ERα reduced MCF-7 (siRNA, MCF-7 ERα−), HS-578 and BT-549 cells (both ER−/PR−)] were exposed to supernatants (collected from first trimester human placental explants and from control BCCL) or to E2 + P4 (estrogen + progesterone) in placental supernatant concentrations and then tested for cell proliferation (number, cell cycle, PCNA), cell-death, cell migration, STAT3 pathway activation and functionality.
Results
Silencing ERα in the MCF-7 cells negated the placental supernatant and E2 + P4 enhancement of cell migration (> 130%, p < 0.05), number (> 120%) and survival (~ 130%). However, it had no such effect on MCF-7-ER− migration, which was still elevated in the presence of placental secretome. ER−/PR− BCCL were unaffected by the hormones, but placental secretome significantly elevated their migration (115%), number (140–170%), STAT3 phosphorylation (~ 180%) and BT-549 STAT3 level. These effects were negated by the STAT3 inhibitor.
Conclusions
Placental supernatant facilitates BCCL malignant characteristics by activating ERα in estrogen responsive cells and STAT3 in ERα- BCCL. This indicates a possible mechanism that may underlie PABC’s advanced state and suggests STAT3 pathway as a therapeutic target for PABC.
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Acknowledgements
This work constitutes a portion of the M.Sc. thesis of Michal Bar, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. We thank Thom Rofe for the English editing.
Funding
This study was supported by the Dr. Leo Mintz Foundation, the internal funds of Sackler Faculty of Medicine, Tel Aviv University, Israel.
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MB: data collection and management, data analysis, manuscript review and editing. OK: placentae collection, manuscript review and editing. MP: placentae collection, manuscript review and editing. AF: placentae collection, manuscript review and editing. LD: project development, analysis and manuscript review and editing. STM: protocol and project development, data analysis, and manuscript writing. ML: project development, analysis and manuscript review and editing.
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All the procedures performed in this study were in accordance with the ethical standards of the ethics Helsinki committee of Meir Hospital and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
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Informed consent was obtained from all individual participants included in the study.
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Bar, M., Komemi, O., Pomeranz, M. et al. Placental supernatants’ enhancement of the metastatic potential of breast cancer cells: is estrogen receptor (ERα) essential for this phenomenon?. Arch Gynecol Obstet 300, 981–991 (2019). https://doi.org/10.1007/s00404-019-05243-4
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DOI: https://doi.org/10.1007/s00404-019-05243-4