Aalam Syed Musheer Mohammed, Ritting Megan L, Ps Hari, Shi Geng-Xian, Shih Kingsley, Dong Yifei, Kalthur Guruprasad, Miao Cao, Yu Yifan, Knapp David Jhf, Eirew Peter, Pellacani Davide, Emperumal Chitra Priya, Wang Hequn, Janus Jeffrey R, Sherman Mark E, Goetz Mathew P, McLaughlin Sarah A, Boughey Judy C, Degnim Amy C, Zeng Haishan, Pandey Akilesh, Radisky Derek C, Sadanandam Anguraj, Kannan Nagarajan
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN, USA.
bioRxiv. 2025 Jul 18:2025.07.15.665005. doi: 10.1101/2025.07.15.665005.
The human mammary epithelium contains a subset of luminal progenitor (LP) cells that are distinct from basal cells in both lineage potential and redox biology. LPs are uniquely equipped to tolerate oxidative stress through glutathione-independent mechanisms and have been implicated as candidate cells of origin in basal-like breast cancers. In this study, we identify the receptor tyrosine kinase (RTK) cKIT (CD117), as a defining feature of LPs and a key mediator of their expansion. cKIT is developmentally restricted to the LP compartment via Polycomb-mediated epigenetic repression in basal and luminal-committed cells. It is expressed in scattered epithelial cells within both ductal and alveolar regions of resting human mammary glands. Using RTK-engineered MCF10A models, we demonstrate that cKIT ligand/stem cell factor (SCF)-activated wildtype cKIT signaling is sufficient to drive proliferation in the absence of epidermal growth factor (EGF) and that cKIT is responsive not only to canonical ligands but also to hydrogen peroxide (HO). In primary human LPs, cKIT is rapidly phosphorylated upon exposure to SCF and HO, with concomitant AKT activation. These responses are enhanced when cKIT and EGFR signaling are co-engaged, suggesting a cooperative mitogenic program. In mammary gland, phosphorylation of the antioxidant enzyme PRDX1 is selectively detected in LPs, consistent with a floodgate model of redox signaling in which transient oxidative inactivation of peroxiredoxins (PRDXs) facilitates RTK signaling under elevated intracellular reactive oxygen species conditions. Clinically, elevated cKIT expression is associated with shorter progression-free survival in certain basal-like breast cancer, supporting a link between LP-like redox signaling states and aggressive tumor behavior. Together, these findings define a redox-integrated RTK signaling axis centered on cKIT that drives LP expansion and is associated with poor outcomes in a subset of basal breast cancers. This work establishes a mechanistic framework for targeting redox-responsive progenitor populations in both regenerative and oncologic context.
人乳腺上皮包含一群管腔祖细胞（LP），其在谱系潜能和氧化还原生物学方面均与基底细胞不同。LP具有独特的能力，可通过不依赖谷胱甘肽的机制耐受氧化应激，并被认为是基底样乳腺癌的候选起源细胞。在本研究中，我们鉴定出受体酪氨酸激酶（RTK）cKIT（CD117）是LP的一个决定性特征及其扩增的关键介质。通过多梳介导的表观遗传抑制，cKIT在发育过程中被限制在基底细胞和已定向分化的管腔细胞中的LP区室。它在静止人乳腺的导管和腺泡区域内的散在上皮细胞中表达。使用RTK工程化的MCF10A模型，我们证明cKIT配体/干细胞因子（SCF）激活的野生型cKIT信号足以在没有表皮生长因子（EGF）的情况下驱动增殖，并且cKIT不仅对经典配体有反应，而且对过氧化氢（HO）也有反应。在原代人LP中，cKIT在暴露于SCF和HO后迅速磷酸化，同时伴有AKT激活。当cKIT和EGFR信号共同激活时，这些反应会增强，表明存在协同的促有丝分裂程序。在乳腺中，抗氧化酶PRDX1的磷酸化在LP中被选择性检测到，这与氧化还原信号的闸门模型一致，即在细胞内活性氧水平升高的条件下，过氧化物酶（PRDX）的瞬时氧化失活促进RTK信号传导。临床上，cKIT表达升高与某些基底样乳腺癌患者较短的无进展生存期相关，支持了类似LP的氧化还原信号状态与侵袭性肿瘤行为之间的联系。总之，这些发现定义了一个以cKIT为中心的氧化还原整合RTK信号轴，该信号轴驱动LP扩增，并与一部分基底乳腺癌的不良预后相关。这项工作建立了一个在再生和肿瘤学背景下靶向氧化还原反应性祖细胞群体的机制框架。
