Tamoxifen Directly Inhibits Platelet Angiogenic Potential and Platelet-Mediated Metastasis.
Platelets, which are mainly known for their role in hemostasis, are now known to play a crucial role in metastasis. Tamoxifen is a selective estrogen receptor modulator that is widely used for the treatment of breast cancer. Tamoxifen and its metabolites have been shown to directly impact platelet function, suggesting that this drug has additional mechanisms of action. The purpose of this study was to determine whether tamoxifen exerts antitumor effects through direct platelet inhibition.



This study found that pretreatment with tamoxifen leads to a significant inhibition of platelet activation. Platelets exposed to tamoxifen released significantly lower amounts of proangiogenic regulator vascular endothelial growth factor. In vitro angiogenesis assays confirmed that tamoxifen pretreatment led to diminished capillary tube formation and decreased endothelial migration. Tamoxifen and its metabolite, 4-hydroxytamoxifen, also significantly inhibited the ability of platelets to promote metastasis in vitro. Using a membrane-based array, we identified several proteins associated with angiogenesis metastasis that were lower in activated releasate from tamoxifen-treated platelets, including angiogenin, chemokine (C-X-C motif) ligand 1, chemokine (C-C motif) ligand 5, epidermal growth factor, chemokine (C-X-C motif) ligand 5, platelet-derived growth factor dimeric isoform BB, whereas antiangiogenic angiopoietin-1 was elevated. Platelets isolated from patients on tamoxifen maintenance therapy were also found to have decreased activation responses, diminished vascular endothelial growth factor release, and lower angiogenic and metastatic potential.



We demonstrate that tamoxifen and its metabolite 4-hydroxytamoxifen directly alter platelet function leading to decreased angiogenic and metastatic potential. Furthermore, this study supports the idea of utilizing targeted platelet therapies to inhibit the platelet's role in angiogenesis and malignancy.
From the Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA (K.E.J., J.A.F., M.D.T., J.R.C., S.E.-H., R.K., K.R.M., J.E.I., E.M.B.); Department of Medicine, Harvard Medical School, Boston, MA (K.E.J., K.R.M., E.L.M., J.E.I., E.M.B.); Vascular Biology Program, Department of Surgery, Children's Hospital Boston, MA (J.E.I.); and Division of Hematology, Dana-Farber Cancer Institute, Boston, MA (E.L.M.).
Kelly E
KE
Johnson
From the Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA (K.E.J., J.A.F., M.D.T., J.R.C., S.E.-H., R.K., K.R.M., J.E.I., E.M.B.); Department of Medicine, Harvard Medical School, Boston, MA (K.E.J., K.R.M., E.L.M., J.E.I., E.M.B.); Vascular Biology Program, Department of Surgery, Children's Hospital Boston, MA (J.E.I.); and Division of Hematology, Dana-Farber Cancer Institute, Boston, MA (E.L.M.).
Jodi A
JA
Forward
From the Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA (K.E.J., J.A.F., M.D.T., J.R.C., S.E.-H., R.K., K.R.M., J.E.I., E.M.B.); Department of Medicine, Harvard Medical School, Boston, MA (K.E.J., K.R.M., E.L.M., J.E.I., E.M.B.); Vascular Biology Program, Department of Surgery, Children's Hospital Boston, MA (J.E.I.); and Division of Hematology, Dana-Farber Cancer Institute, Boston, MA (E.L.M.).
Mason D
MD
Tippy
From the Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA (K.E.J., J.A.F., M.D.T., J.R.C., S.E.-H., R.K., K.R.M., J.E.I., E.M.B.); Department of Medicine, Harvard Medical School, Boston, MA (K.E.J., K.R.M., E.L.M., J.E.I., E.M.B.); Vascular Biology Program, Department of Surgery, Children's Hospital Boston, MA (J.E.I.); and Division of Hematology, Dana-Farber Cancer Institute, Boston, MA (E.L.M.).
Julia R
JR
Ceglowski
From the Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA (K.E.J., J.A.F., M.D.T., J.R.C., S.E.-H., R.K., K.R.M., J.E.I., E.M.B.); Department of Medicine, Harvard Medical School, Boston, MA (K.E.J., K.R.M., E.L.M., J.E.I., E.M.B.); Vascular Biology Program, Department of Surgery, Children's Hospital Boston, MA (J.E.I.); and Division of Hematology, Dana-Farber Cancer Institute, Boston, MA (E.L.M.).
Saleh
S
El-Husayni
From the Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA (K.E.J., J.A.F., M.D.T., J.R.C., S.E.-H., R.K., K.R.M., J.E.I., E.M.B.); Department of Medicine, Harvard Medical School, Boston, MA (K.E.J., K.R.M., E.L.M., J.E.I., E.M.B.); Vascular Biology Program, Department of Surgery, Children's Hospital Boston, MA (J.E.I.); and Division of Hematology, Dana-Farber Cancer Institute, Boston, MA (E.L.M.).
Rajesh
R
Kulenthirarajan
From the Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA (K.E.J., J.A.F., M.D.T., J.R.C., S.E.-H., R.K., K.R.M., J.E.I., E.M.B.); Department of Medicine, Harvard Medical School, Boston, MA (K.E.J., K.R.M., E.L.M., J.E.I., E.M.B.); Vascular Biology Program, Department of Surgery, Children's Hospital Boston, MA (J.E.I.); and Division of Hematology, Dana-Farber Cancer Institute, Boston, MA (E.L.M.).
Kellie R
KR
Machlus
From the Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA (K.E.J., J.A.F., M.D.T., J.R.C., S.E.-H., R.K., K.R.M., J.E.I., E.M.B.); Department of Medicine, Harvard Medical School, Boston, MA (K.E.J., K.R.M., E.L.M., J.E.I., E.M.B.); Vascular Biology Program, Department of Surgery, Children's Hospital Boston, MA (J.E.I.); and Division of Hematology, Dana-Farber Cancer Institute, Boston, MA (E.L.M.).
Erica L
EL
Mayer
From the Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA (K.E.J., J.A.F., M.D.T., J.R.C., S.E.-H., R.K., K.R.M., J.E.I., E.M.B.); Department of Medicine, Harvard Medical School, Boston, MA (K.E.J., K.R.M., E.L.M., J.E.I., E.M.B.); Vascular Biology Program, Department of Surgery, Children's Hospital Boston, MA (J.E.I.); and Division of Hematology, Dana-Farber Cancer Institute, Boston, MA (E.L.M.).
Joseph E
JE
Italiano
From the Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA (K.E.J., J.A.F., M.D.T., J.R.C., S.E.-H., R.K., K.R.M., J.E.I., E.M.B.); Department of Medicine, Harvard Medical School, Boston, MA (K.E.J., K.R.M., E.L.M., J.E.I., E.M.B.); Vascular Biology Program, Department of Surgery, Children's Hospital Boston, MA (J.E.I.); and Division of Hematology, Dana-Farber Cancer Institute, Boston, MA (E.L.M.). ebattinelli@partners.org.
Elisabeth M
EM
Battinelli
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D009362:Neoplasm Metastasis; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D015539:Platelet Activation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D010975:Platelet Aggregation Inhibitors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D013629:Tamoxifen; C016601:afimoxifene
blood platelets; neoplasm metastasis; platelet activation; tamoxifen