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

Purna A Joshi, Prashant Nuthalapati, Dibyo Maiti, Sharon Kwende, Subhajit Maity, Dun Ning
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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 (PDGFRα)-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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脂肪细胞祖细胞是造成乳腺突然内陷后上皮龛持续破坏的主要因素
母乳喂养时间短是产后三阴性乳腺癌死亡率高的一个风险因素。人们对停止母乳喂养和乳腺重塑后持续存在的癌症诱发上皮细胞的内在特性知之甚少。此前,我们发现血小板衍生生长因子受体α(PDGFRα)表达的基质乳腺脂肪细胞祖细胞(MAPs)在成人腺体中分化为管腔上皮祖细胞。在目前的研究中,我们证明 MAP 衍生的管腔祖细胞保留了间充质转录组特征。在模拟短哺乳期的突然内卷模型中,MAP衍生的管腔祖细胞持续存在并主导管腔上皮,经历了转录组学改变,这种改变标志着一种与癌症相关的独特铁代谢状态。与此同时,MAPs 采用了另一种由干扰素介导的促纤维化和侵袭性基质命运。我们的研究发现,MAPs 是突然内陷后病理基质和上皮微环境的主要细胞起源,是产后乳腺癌的潜在治疗靶点。
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