Placental Kisspeptins Differentially Modulate Vital Parameters of Estrogen Receptor-Positive and -Negative Breast Cancer Cells.
Kisspeptins (KPs) are major regulators of trophoblast and cancer invasion. Thus far, limited and conflicting data are available on KP-mediated modulation of breast cancer (BC) metastasis; mostly based on synthetic KP-10, the most active fragment of KP. Here, we report for the first time comprehensive functional effects of term placental KPs on proliferation, adhesion, Matrigel invasion, motility, MMP activity and pro-inflammatory cytokine production in MDA-MB-231 (estrogen receptor-negative) and MCF-7 (estrogen receptor-positive). KPs were expressed at high level by term placental syncytiotrophoblasts and released in soluble form. Placental explant conditioned medium containing KPs (CM) significantly reduced proliferation of both cell types compared to CM without (w/o) KP (CM-w/o KP) in a dose- and time-dependent manner. In MDA-MB-231 cells, placental KPs significantly reduced adhesive properties, while increased MMP9 and MMP2 activity and stimulated invasion. Increased invasiveness of MDA-MB-231 cells after CM treatment was inhibited by KP receptor antagonist, P-234. CM significantly reduced motility of MCF-7 cells at all time points (2-30 hr), while it stimulated motility of MDA-MB-231 cells. These effects were reversed by P-234. Co-treatment with selective ER modulators, Tamoxifen and Raloxifene, inhibited the effect of CM on motility of MCF-7 cells. The level of IL-6 in supernatant of MCF-7 cells treated with CM was higher compared to those treated with CM-w/o KP. Both cell types produced more IL-8 after treatment with CM compared to those treated with CM-w/o KP. Taken together, our observations suggest that placental KPs differentially modulate vital parameters of estrogen receptor-positive and -negative BC cells possibly through modulation of pro-inflammatory cytokine production.
Department of Immunology, Tabriz University of Medical Sciences, Tabriz, 5165683146, Iran.|Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, 5165683146, Iran.
Zahra
Z
Rasoulzadeh
Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, IUMS, Tehran, 1449614535, Iran.|Oncopathology Research Center, Iran University of Medical Sciences, Tehran, 1449614535, Iran.
Roya
R
Ghods
Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, 5165683146, Iran.|Department of Immunology, Tabriz University of Medical Sciences, Tabriz, 5165683146, Iran.
Tohid
T
Kazemi
Immunobiology Research Center, Avicenna Research Institute, ACECR, Tehran, 1177-19615, Iran.
Ebrahim
E
Mirzadegan
SFL Chicken CAM Lab, Institute of Pathophysiology and Immunology, Medical University of Graz, Graz, 8010, Austria.
Nassim
N
Ghaffari-Tabrizi-Wizsy
Institute of Biophysics, Medical University of Graz, Graz, 8010, Austria.
Simin
S
Rezania
Reproductive Biotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, 1177-19615, Iran.
Somaieh
S
Kazemnejad
Reproductive Biotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, 1177-19615, Iran.
Soheila
S
Arefi
Nanobiotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, 1177-19615, Iran.
Jamileh
J
Ghasemi
Nanobiotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, 1177-19615, Iran.
Sedigheh
S
Vafaei
Monoclonal Antibody Research Center, Avicenna Research Institute, ACECR, Tehran, 1177-19615, Iran.
Ahmad-Reza
AR
Mahmoudi
Nanobiotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, 1177-19615, Iran.|Immunology Research Center, Iran University of Medical Sciences, Tehran, 81746-73461, Iran.
Amir-Hassan
AH
Zarnani
D000328:Adult; D017209:Apoptosis; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D059648:Kisspeptins / Q000235:genetics / Q000378:metabolism*; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D014945:Wound Healing; D055815:Young Adult
C106628:KISS1 protein, human; D059648:Kisspeptins; D012333:RNA, Messenger; D011960:Receptors, Estrogen