When tumor suppressor TGFβ meets the HER2 (ERBB2) oncogene

Abstract

Despite its tumor suppressive role in normal mammary epithelial cells, TGFβ has been reported to promote the migration, invasion and survival in breast cancer cells overexpressing the HER2 (ERBB2; neu) oncogene, and to accelerate the metastasis of neu-induced mammary tumors in mice. A clearer understanding of the molecular mechanisms underlying the crosstalk between TGFβ and HER2 has started to emerge. In recent studies reviewed here, the synergistic effect of TGFβ and HER2 on tumor progression has been shown to likely be a combined result of two distinct features: (1) loss of TGFβ's tumor suppressive effect through functional alterations in the anti-mitogenic effect of Smad-mediated transcription, and (2) gain of pro-survival and pro-migratory function through HER2-dependent mechanisms. In HER2-overexpressing breast cancer, this crosstalk results in increased cancer cell proliferation, survival and invasion, accelerated metastasis in animal models, and resistance to chemotherapy and HER2-targeted therapy. Thus, the transformed cellular context imparted by constitutively active HER2 signaling, as a consequence of HER2 gene amplification or overexpression, aborts the tumor suppressive role of TGFβ and facilitated the oncogenic role of this pathway. In turn, TGFβ potentiates oncogenic HER2 signaling by inducing shedding of the ERBB ligands and clustering of HER2 with integrins. Here we discuss recent studies examining Smad-dependent and -independent mechanisms of crosstalk between TGFβ and HER2. Therefore, blockade of TGFβ:HER2 crosstalk may suppress breast cancer progression and metastasis, and enhance the efficiency of conventional therapies in patients with HER2-overexpressing breast cancer.

Figure 1

Mechanisms of the pro-malignant crosstalk between TGFβ and HER2 in breast cancer (based on findings in [, , , –46]). Signals from extracellular TGFβ are transduced into cells that express wild-type TGFβ receptors. Activated TβRI induces a set of Smad-dependent cytostatic gene responses, which are impaired by HER2-mediated alterations of p53 and C/EBPβ activities, as described in [35, 37, 40]. On the other hand, TβRI phosphorylates TACE, resulting in its translocation to the cell surface where it cleaves ERBB pro ligands [45]. ERBB ligands will initiate autocrine and paracrine ERBB signaling in adjacent cells. Ligand-induced ERBB signaling, especially in breast cancer cells overexpressing the ERBB signal amplifier HER2, can subsequently lead to activation of the ShcA, PI3K/Akt, and Src/FAK/integrin signaling cascades to promote cancer progression [–46]. Thus, the crosstalk between TGFβ and HER2 is the functional sum of silenced TGFβ's tumor suppressive effect and enhanced HER2-mediated oncogenic signaling

Figure 2

ALK5^TD signature is associated with clinical outcome in women with breast cancer (figure adapted from [45]). a Hierarchical clustering of 295 breast tumors [48, 49] using 90 overlapping genes with the 271-gene ALK5^TD signature. b Kaplan Meier plots for recurrence-free survival (RFS) and overall survival (OS) comparing the two groups of tumors with and without a correlation with the ALK5^TD signature. c Hierarchical clustering of 22 breast tumors from patients who were treated with navelbine and trastuzumab [50] using 190 overlapping genes with the 271-gene ALK5^TD signature. Cluster 2 shows a positive correlation with the ALK5^TD signature. d Box-and-Whisker plot of Standard Pearson Correlation between the ALK5^TD signature and Clusters determined in c