Estradiol Promotes Breast Cancer Cell Migration via Recruitment and Activation of Neutrophils

Estradiol (E-2) 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 TGF beta 1 is the major chemoattractant for neutrophils. The role of E-2 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 E-2 increased the number of LFA-1(+) neutrophils recruited to the invasive edge of mouse tumors, increased TGF beta 1 secretion and promoted neutrophil infiltration in mammospheres, and induced overexpression of LFA-1 in neutrophils. In zebrafish, in the presence of E-2, neutrophils increased dissemination of ER+ breast cancer cells via LFA-1 and TGF beta 1, 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 TGF beta 1 was overproduced in human breast cancer tissue compared with adjacent normal breast tissue. Thus, E-2 can regulate immune/cancer cell interactions in tumormicroenvironments. Ourresults indicate that extracellular TGF beta 1 is a relevant target in human breast cancer. (C) 2017 AACR.