Breast cancer prevention by short-term inhibition of TGFβ signaling

Cancer prevention has a profound impact on cancer-associated mortality and morbidity. We previously identified TGFβ signaling as a candidate regulator of mammary epithelial cells associated with breast cancer risk. Here, we show that short-term TGFBR inhibitor (TGFBRi) treatment of peripubertal ACI inbred and Sprague Dawley outbred rats induces lasting changes and prevents estrogen- and carcinogen-induced mammary tumors, respectively. We identify TGFBRi-responsive cell populations by single cell RNA-sequencing, including a unique epithelial subpopulation designated secretory basal cells (SBCs) with progenitor features. We detect SBCs in normal human breast tissues and find them to be associated with breast cancer risk. Interactome analysis identifies SBCs as the most interactive cell population and the main source of insulin-IGF signaling. Accordingly, inhibition of TGFBR and IGF1R decrease proliferation of organoid cultures. Our results reveal a critical role for TGFβ in regulating mammary epithelial cells relevant to breast cancer and serve as a proof-of-principle cancer prevention strategy.癌症预防对癌症相关的死亡率与发病率具有深远影响。此前我们已将转化生长因子β（TGFβ）信号通路鉴定为与乳腺癌风险相关的乳腺上皮细胞候选调控因子。本研究显示，对青春期前后的ACI近交系大鼠与Sprague Dawley（SD）远交系大鼠进行短期TGFβ受体（TGFBR）抑制剂（TGFBRi）处理，可分别诱导持久的细胞变化，并预防雌激素与致癌物诱导的乳腺肿瘤。我们通过单细胞RNA测序鉴定了对TGFBRi响应的细胞群，其中包含一类具有祖细胞特性的独特上皮亚群，命名为分泌型基底细胞（SBCs）。我们在正常人类乳腺组织中检测到了SBCs，并发现其与乳腺癌风险相关。互作组分析显示，SBCs是互作活性最强的细胞群，同时也是胰岛素-胰岛素样生长因子（IGF）信号通路的主要来源。据此，同时抑制TGFBR与胰岛素样生长因子1受体（IGF1R）可降低类器官培养物的增殖能力。本研究结果揭示了TGFβ在调控与乳腺癌相关的乳腺上皮细胞中的关键作用，并为癌症预防策略提供了原理验证依据。