Skip to main content

Advertisement

SpringerLink
Log in

Placental supernatants’ enhancement of the metastatic potential of breast cancer cells: is estrogen receptor (ERα) essential for this phenomenon?

  • Gynecologic Oncology
  • Published:
Archives of Gynecology and Obstetrics Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Azim HA Jr, Botteri E, Renne G, Dell'orto P, Rotmensz N, Gentilini O, Sangalli C, Pruneri G, Di Nubila B, Locatelli M, Sotiriou C, Piccart M, Goldhirsch A, Viale G, Peccatori FA (2012) The biological features and prognosis of breast cancer diagnosed during pregnancy: a case–control study. Acta Oncol. 51:653–661

    Article  Google Scholar 

  2. Madaras L, Kovacs KA, Szasz AM, Kenessey I, Tokes AM, Szekely B, Baranyak Z, Kiss O, Dank M, Kulka J (2014) Clinicopathological features and prognosis of pregnancy associated breast cancer - a matched case control study. POR 20:581–590

    CAS  PubMed  Google Scholar 

  3. Azim HA Jr, Brohee S, Peccatori FA, Desmedt C, Loi S, Lambrechts D, Dell'Orto P, Majjaj S, Jose V, Rotmensz N, Ignatiadis M, Pruneri G, Piccart M, Viale G, Sotiriou C (2014) Biology of breast cancer during pregnancy using genomic profiling. Endocr Relat Cancer 21:545–554

    Article  CAS  Google Scholar 

  4. Azim HA Jr, Partridge AH (2014) Biology of breast cancer in young women. Breast Cancer Res 16:427

    Article  Google Scholar 

  5. Azim HA Jr, Michiels S, Bedard PL, Singhal SK, Criscitiello C, Ignatiadis M, Haibe-Kains B, Piccart MJ, Sotiriou C, Loi S (2012) Elucidating prognosis and biology of breast cancer arising in young women using gene expression profiling. Clin Cancer Res 18:1341–1351

    Article  CAS  Google Scholar 

  6. Aboagye-Mathiesen G, Toth FD, Zdravkovic M, Ebbesen P (1994) Production of interferons in human placental trophoblast subpopulations and their possible roles in pregnancy. Clin Diagn Lab Immunol 1:650–659

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Liu SH, Huang JP, Lee RK, Huang MC, Wu YH, Chen CY, Chen CP (2010) Paracrine factors from human placental multipotent mesenchymal stromal cells protect endothelium from oxidative injury via STAT3 and manganese superoxide dismutase activation. Biol Reprod 82:905–913

    Article  CAS  Google Scholar 

  8. Epstein Shochet G, Tartakover Matalon S, Drucker L, Pomeranz M, Fishman A, Rashid G, Oron-Karni V, Pasmanik-Chor M, Lishner M (2011) Hormone-dependent placental manipulation of breast cancer cell migration. Hum Reprod

  9. Epstein Shochet G, Drucker L, Pasmanik-Chor M, Pomeranz M, Fishman A, Tartakover Matalon S, Lishner M (2015) First trimester human placental factors induce breast cancer cell autophagy. Breast Cancer Res Treat 149:645–654

    Article  CAS  Google Scholar 

  10. Guarneri V, Conte P (2009) Metastatic breast cancer: therapeutic options according to molecular subtypes and prior adjuvant therapy. Oncologist 14:645–656

    Article  CAS  Google Scholar 

  11. Epstein Shochet G, Tartakover Matalon S, Drucker L, Pomeranz M, Fishman A, Rashid G, Oron-Karni V, Pasmanik-Chor M, Lishner M (2012) Hormone-dependent placental manipulation of breast cancer cell migration. Hum Reprod (Oxford, England) 27:73–88

    Article  CAS  Google Scholar 

  12. Kastner P, Krust A, Turcotte B, Stropp U, Tora L, Gronemeyer H, Chambon P (1990) Two distinct estrogen-regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B. Embo J. 9:1603–1614

    Article  CAS  Google Scholar 

  13. McDaniel JM, Varley KE, Gertz J, Savic DS, Roberts BS, Bailey SK, Shevde LA, Ramaker RC, Lasseigne BN, Kirby MK, Newberry KM, Partridge EC, Jones AL, Boone B, Levy SE, Oliver PG, Sexton KC, Grizzle WE, Forero A, Buchsbaum DJ, Cooper SJ, Myers RM (2016) Genomic regulation of invasion by STAT3 in triple negative breast cancer. Oncotarget

  14. Epstein Shochet G, Tartakover-Matalon S, Drucker L, Pasmanik-Chor M, Pomeranz M, Fishman A, Lishner M (2014) Placenta-breast cancer cell interactions promote cancer cell epithelial mesenchymal transition via TGFbeta/JNK pathway. Clin Exp Metas 31:961–975

    Article  CAS  Google Scholar 

  15. Tartakover-Matalon S, Mizrahi A, Epstein G, Shneifi A, Drucker L, Pomeranz M, Fishman A, Radnay J, Lishner M (2010) Breast cancer characteristics are modified by first trimester human placenta: in vitro co-culture study. Hum Reprod (Oxford, England) 25:2441–2454

    Article  CAS  Google Scholar 

  16. Fernandopulle SM, Cher-Siangang P, Tan PH (2006) Breast carcinoma in women 35 years and younger: a pathological study. Pathology 38:219–222

    Article  Google Scholar 

  17. Shousha S (2000) Breast carcinoma presenting during or shortly after pregnancy and lactation. Arch Pathol Lab Med 124:1053–1060

    CAS  PubMed  Google Scholar 

  18. Banerjee K, Resat H (2016) Constitutive activation of STAT3 in breast cancer cells: a review. Int J Cancer 138:2570–2578

    Article  CAS  Google Scholar 

  19. McDaniel JM, Varley KE, Gertz J, Savic DS, Roberts BS, Bailey SK, Shevde LA, Ramaker RC, Lasseigne BN, Kirby MK, Newberry KM, Partridge EC, Jones AL, Boone B, Levy SE, Oliver PG, Sexton KC, Grizzle WE, Forero A, Buchsbaum DJ, Cooper SJ, Myers RM (2017) Genomic regulation of invasion by STAT3 in triple negative breast cancer. Oncotarget 8:8226–8238

    Article  Google Scholar 

  20. Xiong A, Yang Z, Shen Y, Zhou J, Shen Q (2014) Transcription factor STAT3 as a novel molecular target for cancer prevention. Cancers 6:926–957

    Article  Google Scholar 

  21. Wang JP, Hielscher A (2017) Fibronectin: how its aberrant expression in tumors may improve therapeutic targeting. J Cancer 8:674–682

    Article  CAS  Google Scholar 

  22. Lee JH, Kim TH, Oh SJ, Yoo JY, Akira S, Ku BJ, Lydon JP, Jeong JW (2013) Signal transducer and activator of transcription-3 (Stat3) plays a critical role in implantation via progesterone receptor in uterus. FASEB J 27:2553–2563

    Article  CAS  Google Scholar 

  23. Shochet GE, Komemi O, Sadeh-Mestechkin D, Pomeranz M, Fishman A, Drucker L, Lishner M, Matalon ST (2016) Heat shock protein-27 (HSP27) regulates STAT3 and eIF4G levels in first trimester human placenta. J Mol Histol 47:555–563

    Article  CAS  Google Scholar 

  24. Bowen JM, Chamley L, Mitchell MD, Keelan JA (2002) Cytokines of the placenta and extra-placental membranes: biosynthesis, secretion and roles in establishment of pregnancy in women. Placenta 23:239–256

    Article  CAS  Google Scholar 

  25. Kauma SW, Herman K, Wang Y, Walsh SW (1993) Differential mRNA expression and production of interleukin-6 in placental trophoblast and villous core compartments. Am J Reprod Immunol. 30:131–135

    Article  CAS  Google Scholar 

Download references

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.

Author information

Author notes

  1. Michael Lishner and Shelly Tartakover Matalon contributed equally.

Authors and Affiliations

  1. Oncogenetic Laboratory, Meir Medical Center, 45 Tschernchovski St., 44281, Kfar Saba, Israel

    Michal Bar, Oded Komemi, Liat Drucker, Michael Lishner & Shelly Tartakover Matalon

  2. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Michal Bar, Oded Komemi, Meir Pomeranz, Ami Fishman, Liat Drucker, Michael Lishner & Shelly Tartakover Matalon

  3. Department of Obstetrics and Gynecology, Meir Medical Center, Kfar Saba, Israel

    Meir Pomeranz & Ami Fishman

  4. Department of Internal Medicine A, Meir Medical Center, Kfar Saba, Israel

    Michael Lishner

Authors
  1. Michal Bar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Oded Komemi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Meir Pomeranz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ami Fishman
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Liat Drucker
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michael Lishner
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shelly Tartakover Matalon
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Corresponding author

Correspondence to Shelly Tartakover Matalon.

Ethics declarations

Conflict of interest

The authors declare that there is no conflict of interest.

Ethical approval

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.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00404-019-05243-4

Keywords

Search

Navigation