Epithelial morphogenesis and oncogenic transformation can cause loss of cell adhesion, and detached cells are eliminated by anoikis. Here, we reveal that transforming growth factor β receptor 3 (TGFBR3) acts as an anoikis mediator through the coordination of activating transcription factor 4 (ATF4). In breast cancer tissues, TGFBR3 is progressively lost, but elevated TGFBR3 is associated with a histologic subtype characterized by cellular adhesion defects. Dissecting the impact of extracellular matrix (ECM) deprivation, we demonstrate that ECM loss promotes TGFBR3 expression, which in turn causes differentiation of cell aggregates, conferring a low-adhesion phenotype, and drives the intrinsic apoptotic pathway. We demonstrate that inhibition of TGFBR3 impairs epithelial anoikis by activating ATF4 signaling. These preclinical findings provide a rationale for therapeutic inhibition of ATF4 in the subgroup of breast cancer patients with low TGFBR3 expression.

中文翻译：

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TGFBR3 通过抑制 ATF4 信号来支持失巢凋亡。

上皮形态发生和致癌转化可导致细胞粘附丧失，脱落细胞被失巢凋亡消除。在这里，我们揭示了转化生长因子 β 受体 3 (TGFBR3) 通过激活转录因子 4 (ATF4) 的协调作为失巢凋亡介质。在乳腺癌组织中，TGFBR3 逐渐丢失，但升高的 TGFBR3 与以细胞粘附缺陷为特征的组织学亚型有关。剖析细胞外基质 (ECM) 剥夺的影响，我们证明 ECM 损失促进 TGFBR3 表达，进而导致细胞聚集体分化，赋予低粘附表型，并驱动内在的凋亡途径。我们证明抑制 TGFBR3 通过激活 ATF4 信号传导损害上皮失巢凋亡。