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bioRxiv · 10.1101/2024.09.08.611930

Adipocyte progenitors are primary contributors to the disrupted epithelial niche that is sustained following abrupt mammary gland involution

Joshi, P. A.·Nuthalapati, P.·Maiti, D.·Kwende, S.·Maity, S.·Ning, D.
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Abstract

A short duration of breastfeeding is a risk factor for the development of high-mortality, postpartum, triple-negative breast cancer. The intrinsic properties of cancer-initiating epithelial cells that persist following breastfeeding cessation and mammary gland remodeling are poorly understood. Previously, we showed that Platelet-Derived Growth Factor Receptor alpha (PDGFR)-expressing stromal mammary adipocyte progenitors (MAPs) differentiate into epithelial luminal progenitors in the adult gland. In the current study, we demonstrate that MAP-derived luminal progenitors retain a mesenchymal transcriptomic signature. In an abrupt involution model that mimics a short breastfeeding duration, MAP-derived luminal progenitors persist and dominate luminal epithelia, undergoing transcriptomic alterations that signify a distinct ferrometabolic state linked to cancer. Concurrently, MAPs adopt an alternative interferon-mediated profibrotic and invasive stromal fate. Our work uncovers MAPs to be the primary cellular origin of a pathological stromal and epithelial microenvironment following abrupt involution, presenting a potential therapeutic target in postpartum breast cancer.

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Joshi, P. A., Nuthalapati, P., Maiti, D., Kwende, S., Maity, S., Ning, D.. 2024-09-10. Adipocyte progenitors are primary contributors to the disrupted epithelial niche that is sustained following abrupt mammary gland involution. https://doi.org/10.1101/2024.09.08.611930

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