CD44 correlates with clinicopathological characteristics and is upregulated by EGFR in breast cancer

Abstract

Cluster of differentiation 44 (CD44), a well-known transmembrane glycoprotein, serves as a promoting factor in the carcinogenesis and progression of a variety of neoplasms. Previous studies have demonstrated that aberrant expression of CD44 was associated with the initiation, invasion, metastasis, and therapy-resistance of breast cancer, but whether there was any association between CD44 and pathological characteristics of breast cancer or epidermal growth factor receptor (EGFR) has not been clearly elucidated. In this study, we utilized public microarray data analysis and tissue microarray technologies to display that CD44 level was enhanced in breast cancer and was significantly correlated with histological grade and the status of estrogen receptor, progesterone receptor and human epidermal growth factor receptor-2 (HER2) and EGFR. Furthermore, mRNA expression of CD44 in breast tumors was positively correlated with basal cytokeratin markers KRT5 and KRT17, but inversely associated with luminal marker FOXA1. Besides, Kaplan-Meier analysis showed that high CD44 mRNA level had adverse impact on the progression-free survival of patients with HER2-expressing or basal-like breast cancer. Functionally, inhibition of EGFR activity by erlotinib impaired the invasion and migration ability of breast cancer cell lines. Western blot assays demonstrated that erlotinib treatment decreased the expression of CD44, accompanied with the reduced protein levels of mesenchymal and cancer stem cell markers. Collectively, this study suggested that the expression of CD44 was upregulated by EGFR pathway and CD44 had a robust impact on the development of breast cancer.

HnRNPM and CD44s expression affects tumor aggressiveness and predicts poor prognosis in breast cancer with axillary lymph node metastases

“…CD44 plays essential roles in tumorigenesis, invasion and metastases, as well as therapy‐response . It has been demonstrated that CD44 is a key downstream target of hnRNPM as well as hnRNPM is critical for the production of the CD44 isoform favoring EMT and metastases . We thus examined the relationship between hnRNPM and CD44 expression.…”

“…HnRNPM is a versatile hnRNP within the M/Q subfamily of proteins that can influence pre‐mRNA splicing by regulating its own pre‐mRNA splicing. Several studies have indicated overexpression of hnRNPM in colorectal carcinoma and breast cancer . HnRNPM is reported as a cell surface receptor expressed in Kupple macrophages that interacts with carcinoembryonic antigen produced by colorectal cancer cells, which is potentially important for tumor metastasis .…”

“…HnRNPM is reported as a cell surface receptor expressed in Kupple macrophages that interacts with carcinoembryonic antigen produced by colorectal cancer cells, which is potentially important for tumor metastasis . HnRNPM could exert its central function in EMT and metastasis of breast cancer by directing the switch in alternative splicing that occurs during EMT . Thus, hnRNPM may function through multiple mechanisms to promote tumor progression.…”

“…The increased hnRNPM expression is associated with high‐grade tumors. Mechanistically hnRNPM may potentiate TGFβ signaling, drive cells to undergo epithelial‐mesenchymal transition (EMT) and positively correlates with breast tumor mesenchymal status as gauged by N‐cadherin expression …”

“…CD44 alternative splicing is differentially regulated by hnRNPM during EMT, resulting in a switch in expression from the variable exon‐containing CD44v isoforms to the standard isoform, CD44s. At the molecular level, hnRNPM directly binds to CD44 pre‐mRNA at GU‐rich sequences and stimulates skipping of CD44 variable exons . HnRNPM plays a central role in establishing breast metastatic nodules in the lung by using different mouse models of breast cancer lung metastasis .…”