Membrane Mucin Muc4 promotes blood cell association with tumor cells and mediates efficient metastasis in a mouse model of breast cancer

Abstract

Mucin-4 (Muc4) is a large cell surface glycoprotein implicated in the protection and lubrication of epithelial structures. Previous studies suggest that aberrantly expressed Muc4 can influence the adhesiveness, proliferation, viability and invasiveness of cultured tumor cells, as well as the growth rate and metastatic efficiency of xenografted tumors. While it has been suggested that one of the major mechanisms by which Muc4 potentiates tumor progression is via its engagement of the ErbB2/HER2 receptor tyrosine kinase, other mechanisms exist and remain to be delineated. Moreover, the requirement for endogenous Muc4 for tumor growth progression has not been previously explored in the context of gene ablation. To assess the contribution of endogenous Muc4 to mammary tumor growth properties, we first created a genetically-engineered mouse line lacking functional Muc4 (Muc4ko), and then crossed these animals with the NDL model of ErbB2-induced mammary tumorigenesis. We observed that Muc4ko animals are fertile and develop normally, and adult mice exhibit no overt tissue abnormalities. In tumor studies, we observed that although some markers of tumor growth such as vascularity and cyclin D1 expression are suppressed, primary mammary tumors from Muc4ko/NDL female mice exhibit similar latencies and growth rates as Muc4wt/NDL animals. However, the presence of lung metastases is markedly suppressed in Muc4ko/NDL mice. Interestingly, histological analysis of lung lesions from Muc4ko/NDL mice revealed a reduced association of disseminated cells with red and white blood cells. Moreover, isolated cells derived from Muc4ko/NDL tumors interact with fewer blood cells when injected directly into the vasculature or diluted into blood from wild type mice. We further observed that blood cells more efficiently promote the viability of non-adherent Muc4wt/NDL cells than Muc4ko/NDL cells. Together, our observations suggest that Muc4 may facilitate metastasis by promoting the association of circulating tumor cells with blood cells to augment tumor cell survival in circulation.

Integrated analyses of murine breast cancer models reveal critical parallels with human disease

“…10). Notably we identified mutations within Mucin 4 ( Muc4 ), which are potentially impactful due to Muc4 ’s emerging roles in Her2-positive cancer and metastasis 25 . Interestingly, we observed that PyMT-induced tumors had more SNVs in the coding regions of the genome.…”

Integrated sequence and gene expression analysis of mouse models of breast cancer reveals critical events with human parallels

“…For instance, the MMTV-Neu model had no genes with shared mutations in all samples and only five genes containing a coding, non-synonymous mutation in more than one sample ( Figure S6). Notably we identified mutations within Mucin 4 (Muc4) which are potentially impactful due to Muc4's emerging roles in Her2 positive cancer and metastasis 16 . Interestingly, we observed that PyMT induced tumors had more SNVs in the coding regions of the genome.…”

MicroRNA‑mRNA integrated analysis based on a case of well‑differentiated thyroid cancer with both metastasis and metastatic recurrence

“…Another two molecules involved in WDTC progression were also related to cancer cell stemness. As reported in ovarian carcinoma (45), MUC4 can induce epithelial-mesenchymal transition, and it can enhance the invasion of tumors in pancreatic and breast cancers (46,47). miR-30a-5p, the only overlapped miRNA in metastatic lesions, is reported to be associated with cancer metastasis.…”