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Open AccessArticle

Paracrine Signaling from Breast Cancer Cells Causes Activation of ID4 Expression in Tumor-Associated Macrophages

1
IRCCS Regina Elena National Cancer Institute, Oncogenomic and Epigenetic Unit, Via E. Chianesi, 53, 00144 Rome, Italy
2
IRCCS Regina Elena National Cancer Institute, Pathology Department,Via E. Chianesi, 53, 00144 Rome, Italy
3
Department of Anatomical, Histological, Forensic & Orthopaedic Sciences, Section of Histology & Medical Embryology, Sapienza University of Rome, Via A. Scarpa, 16, 00161 Rome, Italy
4
Laboratory affiliated with Istituto Pasteur Italia-Fondazione Cenci Bolognetti, 00161 Rome, Italy
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Cells 2020, 9(2), 418; https://doi.org/10.3390/cells9020418
Received: 15 November 2019 / Revised: 3 February 2020 / Accepted: 8 February 2020 / Published: 11 February 2020
Background: Tumor-associated macrophages (TAMs) constitute a major portion of the leukocyte infiltrate found in breast cancer (BC). BC cells may reprogram TAMs in a pro-angiogenic and immunosuppressive sense. We previously showed that high expression of the ID4 protein in triple-negative BC cells leads to the induction of a proangiogenic program in TAMs also through the downregulation of miR-107. Here, we investigated the expression and function of the ID4 protein in TAMs. Methods: Human macrophages obtained from peripheral blood-derived monocytes (PBDM) and mouse RAW264.7 cells were used as macrophage experimental systems. ID4-correlated mRNAs of the TCGA and E-GEOD-18295 datasets were analyzed. Results: We observed that BC cells determine a paracrine induction of ID4 expression and activation of the ID4 promoter in neighboring macrophages. Interestingly, ID4 expression is higher in macrophages associated with invasive tumor cells compared to general TAMs, and ID4-correlated mRNAs are involved in various pathways that were previously reported as relevant for TAM functions. Selective depletion of ID4 expression in macrophages enabled validation of the ability of ID4 to control the expression of YAP1 and of its downstream targets CTGF and CYR61. Conclusion: Collectively, our results show that activation of ID4 expression in TAMs is observed as a consequence of BC cell paracrine activity and could participate in macrophage reprogramming in BC.
Keywords: Tumor-associated-macrophages; TAMs; breast cancer; BLBC; TNBC; ID4; YAP1; CTGF; CYR61; VEGFA; ARNT Tumor-associated-macrophages; TAMs; breast cancer; BLBC; TNBC; ID4; YAP1; CTGF; CYR61; VEGFA; ARNT
MDPI and ACS Style

Donzelli, S.; Sacconi, A.; Turco, C.; Gallo, E.; Milano, E.; Iosue, I.; Blandino, G.; Fazi, F.; Fontemaggi, G. Paracrine Signaling from Breast Cancer Cells Causes Activation of ID4 Expression in Tumor-Associated Macrophages. Cells 2020, 9, 418.

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