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Estradiol promotes breast cancer cell migration via recruitment and activation of neutrophils
Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology. (Charlotta Dabrosin)
Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology. (Charlotta Dabrosin)
Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.ORCID iD: 0000-0001-7191-0018
2017 (English)In: Cancer Immunology research, ISSN 2326-6066, Vol. 5, no 3, p. 234-247, article id 28159748Article in journal (Refereed) Published
Abstract [en]

Estradiol (E2) plays a key role in breast cancer progression. Most breast cancer recurrences express the estrogen receptor (ER), but nearly 50% of patients are resistant to antiestrogen therapy. Novel therapeutic targets of ER-positive breast cancers are needed. Protumoral neutrophils expressing the lymphocyte function-associated antigen 1 (LFA-1) integrin may mediate cancer metastasis, and TGFβ1 is the major chemoattractant for neutrophils. The role of E2 in neutrophil–ER+ breast cancer cell interactions is unknown. We studied this in vivo using murine breast cancers in immunocompetent mice and human breast cancers in nude mice. Cell dissemination was evaluated in a zebrafish model, and microdialysis of breast cancer patients was performed. In vitro studies were done with mammosphere cultures of breast cancer cells and human neutrophils. We found that E2 increased the number of LFA-1+ neutrophils recruited to the invasive edge of mouse tumors, increased TGFβ1 secretion and promoted neutrophil infiltration in mammospheres, and induced overexpression of LFA-1 in neutrophils. In zebrafish, in the presence of E2, neutrophils increased dissemination of ER+ breast cancer cells via LFA-1 and TGFβ1, thus causing noninvasive cancer cells to be highly metastatic. Time-lapse imaging in zebrafish revealed close interactions of neutrophils with cancer cells, which drove breast cancer metastasis. We also found that extracellular TGFβ1 was overproduced in human breast cancer tissue compared with adjacent normal breast tissue. Thus, E2 can regulate immune/cancer cell interactions in tumor microenvironments. Our results indicate that extracellular TGFβ1 is a relevant target in human breast cancer.

Place, publisher, year, edition, pages
American Association for Cancer Research , 2017. Vol. 5, no 3, p. 234-247, article id 28159748
National Category
Clinical Medicine
Identifiers
URN: urn:nbn:se:liu:diva-135330DOI: 10.1158/2326-6066.CIR-16-0150ISI: 000396023000006PubMedID: 28159748OAI: oai:DiVA.org:liu-135330DiVA, id: diva2:1081078
Funder
Swedish Cancer Society, 2015/309Swedish Research Council, 2013-2457Linköpings universitet
Note

Funding agencies: Swedish Cancer Society [2015/309]; Swedish Research Council [2013-2457]; LiU-Cancer; Research Funds of Linkoping University Hospital

Available from: 2017-03-13 Created: 2017-03-13 Last updated: 2024-02-21

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Vazquez Rodriguez, GabrielaAbrahamsson, AnnelieDabrosin, Charlotta

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Vazquez Rodriguez, GabrielaAbrahamsson, AnnelieJensen, LasseDabrosin, Charlotta
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Division of Surgery, Orthopedics and OncologyFaculty of Medicine and Health SciencesDepartment of OncologyDivision of Cardiovascular MedicineDepartment of Clinical Pharmacology
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