CPEB1 mediates epithelial-to-mesenchyme transition and breast cancer metastasis

Abstract

In mouse mammary epithelial cells, CPEB1 mediates the apical localization of ZO-1 mRNA, which encodes a critical tight junction component. In mice lacking CPEB1 and in cultured cells from which CPEB has been depleted, randomly distributed ZO-1 mRNA leads to the loss of cell polarity. We have investigated whether this diminution of polarity results in an epithelial-to-mesenchyme (EMT) transition and possible increased metastatic potential. Here, we show that CPEB1-depleted mammary epithelial cells alter their gene expression profile in a manner consistent with an EMT and also become motile, which are made particularly robust when cells are treated with TGF-β, an enhancer of EMT. CPEB1-depleted mammary cells become metastatic to the lung following injection into mouse fat pads while ectopically-expressed CPEB1 prevents metastasis. Surprisingly, CPEB1 depletion causes some EMT/metastasis-related mRNAs to have shorter poly(A) tails while other mRNAs to have longer poly(A) tails. Matrix metalloproteinase 9 (MMP9) mRNA, which encodes a metastasis-promoting factor, undergoes poly(A) lengthening and enhanced translation upon CPEB reduction. Moreover, in human breast cancer cells that become progressively more metastatic, CPEB1 is reduced while MMP9 becomes more abundant. These data suggest that at least in part, CPEB1 regulation of MMP9 mRNA expression mediates metastasis of breast cancer cells.

Regulation of the Expression of Cytoplasmic Polyadenylation Element Binding Proteins for the Treatment of Cancer

“…In human breast cancer cells that become progressively more metastatic, CPEB1 is reduced, while MMP-9 becomes abundant (33). CPEB1-depleted mammary cells become metastatic to the lung following injection into mouse fat pads, while ectopically expressed CPEB1 prevents metastasis (33). All these results suggest the reduced CPEB1 levels might be related to the tumor formation and metastasis of the transformed breast cells (5).…”

“…In addition, upon CPEB1 reduction, matrix metalloproteinase 9 (MMP-9) mRNA, which encodes a metastasis-promoting factor, undergoes poly(A) lengthening and enhanced translation (33). In human breast cancer cells that become progressively more metastatic, CPEB1 is reduced, while MMP-9 becomes abundant (33). CPEB1-depleted mammary cells become metastatic to the lung following injection into mouse fat pads, while ectopically expressed CPEB1 prevents metastasis (33).…”

“…CPEB1 interacts with Twist1 mRNA and down-regulates its expression; in the absence of CPEB1, Twist1 mRNA translation is elevated, which leads to EMT and metastasis (5,36). In addition, upon CPEB1 reduction, matrix metalloproteinase 9 (MMP-9) mRNA, which encodes a metastasis-promoting factor, undergoes poly(A) lengthening and enhanced translation (33). In human breast cancer cells that become progressively more metastatic, CPEB1 is reduced, while MMP-9 becomes abundant (33).…”

“…The loss of cell polarity can lead to epithelialmesenchymal transition (EMT) and the cells dedifferentiate and become metastatic (34). The CPEB1-depleted mammary epithelial cells alter their gene expression profile in a manner consistent with an EMT and also become motile, which are made particularly robust when cells are treated with transforming growth factor-β, an enhancer of EMT (33). Twist, a transcription factor, plays an important role in EMT and metastasis (35).…”

“…The reduced levels of CPEB1 have also been associated with the capacity of these malignant cells to promote invasion and angiogenesis (22,32). In the absence of CPEB1, mammary epithelial cells lose cell polarity (33). The loss of cell polarity can lead to epithelialmesenchymal transition (EMT) and the cells dedifferentiate and become metastatic (34).…”