Estradiol Promotes Breast Cancer Cell Migration via Recruitment and Activation of Neutrophils.
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 E2in neutrophil-ER+breast cancer cell interactions is unknown. We studied thisin vivousing 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 vitrostudies were done with mammosphere cultures of breast cancer cells and human neutrophils. We found that E2increased 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, E2can regulate immune/cancer cell interactions in tumor microenvironments. Our results indicate that extracellular TGFβ1 is a relevant target in human breast cancer.Cancer Immunol Res; 5(3); 234-47. ©2017 AACR.
Department of Oncology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
Gabriela
G
Vazquez Rodriguez
Department of Oncology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
Annelie
A
Abrahamsson
Department of Medicine and Health Sciences, Linköping University, Linköping, Sweden.
Lasse Dahl Ejby
LD
Jensen
Department of Oncology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden. charlotta.dabrosin@liu.se.
Charlotta
C
Dabrosin
D000818:Animals; D001943:Breast Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects* / Q000276:immunology*; D004195:Disease Models, Animal; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression; D006801:Humans; D016169:Lymphocyte Function-Associated Antigen-1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009362:Neoplasm Metastasis; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000276:immunology; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology*; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays; D015027:Zebrafish
D016169:Lymphocyte Function-Associated Antigen-1; D011960:Receptors, Estrogen; D053773:Transforming Growth Factor beta1; D004958:Estradiol