Cxcr2 is required for ductal outgrowth and shapes the stromal microenvironment in postnatal mammary gland development
- 1University of Notre Dame
Abstract
Mammary gland development requires coordinated signaling between epithelial and stromal compartments. While CXC chemokine receptor 2 (CXCR2) is known to regulate inflammatory and tissue remodeling processes in disease, including breast cancer, its role in mammary gland morphogenesis is not well understood. Here, we examined postnatal mammary gland development in germline Cxcr2 knockout mice. Loss of Cxcr2 resulted in delayed ductal outgrowth, reduced epithelial area, and altered stromal architecture, including decreased adipocyte size and increased collagen deposition, despite preserved branching organization. These defects occurred in the context of severe systemic immune dysregulation, marked by expansion of granulocytic populations and loss of adaptive immune cells. Together, our findings indicate that CXCR2 indirectly regulates mammary gland development through coordination between the epithelium and stroma, rather than acting through epithelial cell-intrinsic mechanisms. Because the same myeloid expansion, immune suppression, and collagen-rich stromal remodeling that CXCR2 controls during normal development are hallmarks of the pro-tumorigenic breast microenvironment, these findings establish CXCR2 as a regulator of the immune and stromal landscape of the mammary gland and provide a developmental framework for understanding its contributions to the breast tumor microenvironment.
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BibTeX
@misc{flatt2026cxcr2,
title = {{Cxcr2 is required for ductal outgrowth and shapes the stromal microenvironment in postnatal mammary gland development}},
author = {C. L. Flatt and E. Powers and A. Rosenberg and M. O'Hare and A. Bui and A. Dharshika Shangaradas and J. Wu and G. L. Niebur and J. Li and L. Littlepage},
howpublished = {bioRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.08.765094},
url = {https://www.biorxiv.org/content/10.64898/2026.11.08.765094v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Cxcr2 is required for ductal outgrowth and shapes the stromal microenvironment in postnatal mammary gland development
AU - C. L. Flatt
AU - E. Powers
AU - A. Rosenberg
AU - M. O'Hare
AU - A. Bui
AU - A. Dharshika Shangaradas
AU - J. Wu
AU - G. L. Niebur
AU - J. Li
AU - L. Littlepage
PY - 2026
DA - 2026/11/08
PB - bioRxiv
DO - 10.64898/2026.11.08.765094
UR - https://www.biorxiv.org/content/10.64898/2026.11.08.765094v1
AB - Mammary gland development requires coordinated signaling between epithelial and stromal compartments. While CXC chemokine receptor 2 (CXCR2) is known to regulate inflammatory and tissue remodeling processes in disease, including breast cancer, its role in mammary gland morphogenesis is not well understood. Here, we examined postnatal mammary gland development in germline Cxcr2 knockout mice. Loss of Cxcr2 resulted in delayed ductal outgrowth, reduced epithelial area, and altered stromal architecture, including decreased adipocyte size and increased collagen deposition, despite preserved branching organization. These defects occurred in the context of severe systemic immune dysregulation, marked by expansion of granulocytic populations and loss of adaptive immune cells. Together, our findings indicate that CXCR2 indirectly regulates mammary gland development through coordination between the epithelium and stroma, rather than acting through epithelial cell-intrinsic mechanisms. Because the same myeloid expansion, immune suppression, and collagen-rich stromal remodeling that CXCR2 controls during normal development are hallmarks of the pro-tumorigenic breast microenvironment, these findings establish CXCR2 as a regulator of the immune and stromal landscape of the mammary gland and provide a developmental framework for understanding its contributions to the breast tumor microenvironment.
ER -