Paracrine Crosstalk between Fibroblasts and ER+ Breast Cancer Cells Creates an IL1β-Enriched Niche that Promotes Tumor Growth

• Published in: iScience Vol. 19; pp. 388 - 401
• Main Authors: Chatterjee, Sumanta, Bhat, Vasudeva, Berdnikov, Alexei, Liu, Jiahui, Zhang, Guihua, Buchel, Edward, Safneck, Janice, Marshall, Aaron J., Murphy, Leigh C., Postovit, Lynne-Marie, Raouf, Afshin
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27.09.2019; Elsevier
• Subjects: Cancer; Functional Aspects of Cell Biology; Molecular Mechanism of Behavior; Molecular Mechanism of Behavior; Functional Aspects of Cell Biology; Cancer
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2019.07.034

Breast cancer-induced activated fibroblasts support tumor progression. However, the role of normal fibroblasts in tumor progression remains controversial. In this study, we used modified patient-derived organoid cultures and demonstrate that constitutively secreted cytokines from normal breast fibroblasts initiate a paracrine signaling mechanism with estrogen receptor-positive (ER+) breast cancer cells, which results in the creation of an interleukin (IL)-1β-enriched microenvironment. We found that this paracrine signaling mechanism is shared between normal and activated fibroblasts. Interestingly, we observed that in reconstructed tumor microenvironment containing autologous ER+ breast cancer cells, activated fibroblasts, and immune cells, tamoxifen is more effective in reducing tumor cell proliferation when this paracrine signaling is blocked. Our findings then suggest that ER+ tumor cells could create a growth-promoting environment without activating stromal fibroblasts and that in breast-conserving surgeries, normal fibroblasts could be a significant modulator of tumor recurrence by enhancing the proliferation of residual breast cancer cells in the tumor-adjacent breast tissue. [Display omitted] •Normal fibroblast-cancer cell interaction promotes tumor progression•Paracrine signaling common to normal and activated fibroblasts promotes drug resistance•Fibroblast-secreted factors create an IL1β-enriched niche for ER+ breast cancer cell growth Molecular Mechanism of Behavior; Functional Aspects of Cell Biology; Cancer