JUNB governs a feed-forward network of TGFβ signaling that aggravates breast cancer invasion

Abstract

It is well established that transforming growth factor-β (TGFβ) switches its function from being a tumor suppressor to a tumor promoter during the course of tumorigenesis, which involves both cell-intrinsic and environment-mediated mechanisms. We are interested in breast cancer cells, in which SMAD mutations are rare and interactions between SMAD and other transcription factors define pro-oncogenic events. Here, we have performed chromatin immunoprecipitation (ChIP)-sequencing analyses which indicate that the genome-wide landscape of SMAD2/3 binding is altered after prolonged TGFβ stimulation. De novo motif analyses of the SMAD2/3 binding regions predict enrichment of binding motifs for activator protein (AP)1 in addition to SMAD motifs. TGFβ-induced expression of the AP1 component JUNB was required for expression of many late invasion-mediating genes, creating a feed-forward regulatory network. Moreover, we found that several components in the WNT pathway were enriched among the late TGFβ-target genes, including the invasion-inducing WNT7 proteins. Consistently, overexpression of WNT7A or WNT7B enhanced and potentiated TGFβ-induced breast cancer cell invasion, while inhibition of the WNT pathway reduced this process. Our study thereby helps to explain how accumulation of pro-oncogenic stimuli switches and stabilizes TGFβ-induced cellular phenotypes of epithelial cells.

Intracellular and extracellular TGF-β signaling in cancer: some recent topics

“…In several cancers, for example, inactivation of SMAD4 gene serves as the cellintrinsic switch, causing the escape from the cytostatic effects of TGF-β. However, Smad4-intact cancer cells, such as breast cancer cells, have a different cell-intrinsic switch of TGF-β signaling: accumulation of pro-oncogenic stimuli switches and stabilizes the TGF-β-induced migratory and invasive phenotype of Ras-transformed mammary epithelial cells [165].…”

Roles of Wnt7a in embryo development, tissue homeostasis, and human diseases

“…These findings demonstrate that Wnt7a promotes ovarian cancer initiation and progression in an autocrinal and paracrinal manner. In breast cancer, Wnt7a is a target gene of TGF‐β and enhances both basal and TGF‐β‐induced invasion . Wnt7a derived from breast cancer cells also activates fibroblasts dependent on TGF‐β signaling but not β‐catenin pathway, thereby promoting cell invasion and metastasis .…”

“…In breast cancer, Wnt7a is a target gene of TGF-β and enhances both basal and TGF-β-induced invasion. 97 Wnt7a derived from breast cancer cells also activates fibroblasts dependent on TGF-β signaling but not β-catenin pathway, thereby promoting cell invasion and metastasis. 98 Consistently, high Wnt7a expression in breast cancers is also correlated with unfavorable prognosis.…”

Wnt signaling in human and mouse breast cancer: Focusing on Wnt ligands, receptors and antagonists

“…Transforming growth factor‐β pathways have crosstalk with the Wnt pathway in EMT induction (Figure ). TGF‐β induces Wnt7a/7b through Smad2/3, which inversely enhances TGF‐β‐induced EMT of mammary epithelial cells . Moreover, TGF‐β can activate the β‐catenin pathway to induce EMT through other molecules such as P38 in a Wnt ligand‐nondependent method .…”

“…TGF-β induces Wnt7a/7b through Smad2/3, which inversely enhances TGF-β-induced EMT of mammary epithelial cells. 63 Moreover, TGF-β can activate the β-catenin pathway to induce EMT through other molecules such as P38 in a Wnt ligand-nondependent method. 64 Both TGF-β and β-catenin induce EMT involving a series of EMT transcription factors including Snail, Slug and Twist.…”