Breast cancers are classified into five intrinsic subtypes and 10 integrative clusters based on gene expression patterns and genomic aberrations, respectively. Although the cell-of-origin, adaptive plasticity, and genomic aberrations shape dynamic transcriptomic landscape during cancer progression, how interplay between these three core elements governs obligatory steps for a productive cancer progression is unknown. Here, we used genetic ancestry-mapped immortalized breast epithelial cell lines generated from breast biopsies of healthy women that share gene expression profiles of luminal A, normal-like, and basal-like intrinsic subtypes of breast cancers and breast cancer relevant oncogenes to develop breast cancer progression model. Using flow cytometry, mammosphere growth, signaling pathway, DNA damage response, and in vivo tumorigenicity assays, we provide evidence that establishes cell context–dependent effects of oncogenes in conferring plasticity, self-renewal/differentiation, intratumor heterogeneity, and metastatic properties. In contrast, oncogenic aberrations, independent of cell context, shaped response to DNA damage-inducing agents. Collectively, this study reveals how the same set of genomic aberration can have distinct effects on tumor characteristics based on cell-of-origin of tumor and highlights the need to utilize multiple “normal” epithelial cell types to decipher oncogenic properties of a gene of interest. In addition, by creating multiple isogenic cell lines ranging from primary cells to metastatic variants, we provide resources to elucidate cell-intrinsic properties and cell-oncogene interactions at various stages of cancer progression. Implications: Our findings demonstrate that how an interplay between the normal cell type that encountered genomic aberrations and type of genomic aberration influences heterogeneity, self-renewal/differentiation, and tumor properties including propensity for metastasis.

中文翻译：

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细胞背景和基因组畸变之间的双向调控交叉影响了乳腺肿瘤的发生

根据基因表达模式和基因组畸变，乳腺癌分别分为 5 种内在亚型和 10 种综合集群。尽管细胞起源、适应性可塑性和基因组畸变在癌症进展过程中塑造了动态转录组学的格局，但这三个核心要素之间的相互作用如何控制有效的癌症进展的强制性步骤尚不清楚。在这里，我们使用了从健康女性的乳腺活检中产生的遗传祖先映射的永生化乳腺上皮细胞系，这些细胞系共享了 luminal A、正常样和基底样乳腺癌内在亚型和乳腺癌相关癌基因的基因表达谱来发展乳腺癌。癌症进展模型。使用流式细胞仪、乳腺球生长、信号通路、DNA损伤反应、和体内致瘤性测定，我们提供的证据表明癌基因在赋予可塑性、自我更新/分化、肿瘤内异质性和转移特性方面的细胞环境依赖性作用。相比之下，独立于细胞环境的致癌畸变塑造了对 DNA 损伤诱导剂的反应。总的来说，这项研究揭示了同一组基因组畸变如何对基于肿瘤细胞来源的肿瘤特征产生不同的影响，并强调需要利用多种“正常”上皮细胞类型来破译感兴趣基因的致癌特性. 此外，通过创建从原代细胞到转移变体的多种同基因细胞系，我们提供资源来阐明癌症进展不同阶段的细胞内在特性和细胞-癌基因相互作用。启示：我们的研究结果表明，遇到基因组畸变的正常细胞类型和基因组畸变类型之间的相互作用如何影响异质性、自我更新/分化和肿瘤特性，包括转移倾向。