MUC4 Overexpression Augments Cell Migration and Metastasis through EGFR Family Proteins in Triple Negative Breast Cancer Cells

Abstract

IntroductionCurrent studies indicate that triple negative breast cancer (TNBC), an aggressive breast cancer subtype, is associated with poor prognosis and an early pattern of metastasis. Emerging evidence suggests that MUC4 mucin is associated with metastasis of various cancers, including breast cancer. However, the functional role of MUC4 remains unclear in breast cancers, especially in TNBCs.MethodIn the present study, we investigated the functional and mechanistic roles of MUC4 in potentiating pathogenic signals including EGFR family proteins to promote TNBC aggressiveness using in vitro and in vivo studies. Further, we studied the expression of MUC4 in invasive TNBC tissue and normal breast tissue by immunostaining.ResultsMUC4 promotes proliferation, anchorage-dependent and-independent growth of TNBC cells, augments TNBC cell migratory and invasive potential in vitro, and enhances tumorigenicity and metastasis in vivo. In addition, our studies demonstrated that MUC4 up-regulates the EGFR family of proteins, and augments downstream Erk1/2, PKC-γ, and FAK mediated oncogenic signaling. Moreover, our studies also showed that knockdown of MUC4 in TNBC cells induced molecular changes suggestive of mesenchymal to epithelial transition. We also demonstrated in this study, for the first time, that knockdown of MUC4 was associated with reduced expression of EGFR and ErbB3 (EGFR family proteins) in TNBC cells, suggesting that MUC4 uses an alternative to ErbB2 mechanism to promote aggressiveness. We further demonstrate that MUC4 is differentially over-expressed in invasive TNBC tissues compared to normal breast tissue.ConclusionsMUC4 mucin expression is associated with TNBC pathobiology, and its knockdown reduced aggressiveness in vitro, and tumorigenesis and metastasis in vivo. Overall, our findings suggest that MUC4 mucin promotes invasive activities of TNBC cells by altering the expression of EGFR, ErbB2, and ErbB3 molecules and their downstream signaling.

Periodic Mechanical Stress Activates PKCδ-Dependent EGFR Mitogenic Signals in Rat Chondrocytes via PI3K-Akt and ERK1/2

“…Some studies showed that EGFR was required for PKC activation in other cell types in response to various stimuli [44,45]. Interestingly, instead of being activated by an EGFRdependent mechanism, the inhibition of cyclic mechanical stress-stimulated EGFR by rottlerin or shRNA targeted to PKCδ suggested that PKCδ might be responsible for the initial EGFR activation in the present study.…”

Molecular alterations that drive breast cancer metastasis to bone

“…A separate study demonstrated that knockdown of MUC4 in breast cancer cells leads to molecular and biochemical alterations that are necessary for EMT, including reduced expression of mesenchymal markers such as vimentin and vitronectin and increased expression of the epithelial marker cytokeratin 18. 40 These data suggest that MUC4 has an important role in EMT, transforming breast cancer cells into a more migratory and aggressive phenotype.…”

MiR-150-5p Suppresses Colorectal Cancer Cell Migration and Invasion through Targeting MUC4

“…It was reported that the dysregulation of miR-150-5p performed diverse functions in different types of cancer (Wu et al, 2010;Srivastava et al, 2011;Huang et al, 2013;Cao et al, 2014). Previously, it was reported that the serum exosomal levels of miR-150-5p was significantly higher in primary CRC patients than in healthy controls, and was significantly down-regulated after surgical resection of tumors, suggesting miR-150-5p is a promising biomarkers for non-invasive diagnosis of the disease (Ogata-Kawata et al, 2014). However, it was uncovered in other researchers that CRC tumors had reduced levels of miR-150-5p expression compared with paired non-cancerous tissue, and miR-150-5p was suggested to be considered as a potential biomarker associated with the prognosis in CRC .…”

“…Furthermore, increasing evidence also indicate MUC4 is critical for the progression of other malignancies (Ponnusamy et al, 2008;Rachagani et al, 2012;Mukhopadhyay et al, 2013). It is proposed that MUC4 may be regulated at the transcriptional level via the transforming growth factorβand epidermal growth factor pathways among others (Perrais et al, 2001;Andrianifahanana et al, 2005), and at the epigenetic level via DNA methylation and histone modifications (Vincent et al, 2008).…”