MUC1 induces acquired chemoresistance by upregulating ABCB1 in EGFR-dependent manner

Abstract

Chemoresistance contributes to cancer relapse and increased mortality in a variety of cancer types, raising a pressing need to better understand the underlying mechanism. MUC1 is abnormally overexpressed in numerous carcinomas and associated with poor prognosis. However, the functional significance of MUC1 in chemoresistance has not been fully elucidated. Here, we showed that MUC1 expression was considerably induced in cells that had acquired chemoresistance at both transcriptional and post-translational levels. Using gain- and loss-of function approaches, we demonstrated a critical role of MUC1 in induction of drug resistance. Through stimulation of EGFR activation and nuclear translocation, MUC1 increased the expression of ATP-binding cassette transporter B1 (ABCB1). Remarkably, targeted suppression of EGFR or ABCB1 by both shRNAs and inhibitors effectively reversed chemoresistance. Moreover, co-administration of the inhibitors of MUC1–EGFR–ABCB1 with paclitaxel significantly blocked not only tumor growth but also relapse in xenograft mouse model. Our data collectively support a model in which MUC1 induces acquired chemotherapy resistance by upregulating ABCB1 in an EGFR-dependent manner, providing a novel molecular basis of using the EGFR inhibitor in MUC1-positive cancers to prevent chemotherapy resistance.

Downregulation of leucine‐rich repeats and immunoglobulin‐like domains 1 by microRNA‐20a modulates gastric cancer multidrug resistance

“…Western blotting demonstrated that downregulation of LRIG1 or upregulation of miR‐20a significantly enhanced EGFR activity, and increased p‐AKT (phospho‐AKT) and p‐ERK1/2 (phospho‐ERK1/2) protein expression (Figure D). In addition, P‐gp and Bcl‐2, as important downstream molecules of EGFR signal, were remarkably increased after LRIG1 knockdown or miR‐20a upregulation . Taken together, these results indicated that the miR‐20a/LRIG1 axis might regulate GC cell drug resistance by increasing EGFR activity and through secondary accelerating PI3K/AKT and MAPK/ERK signaling pathways (Figure E).…”

Potential Interplay of the Gatipotuzumab Epitope TA-MUC1 and Estrogen Receptors in Ovarian Cancer

“…Nuclear MUC-1-C binds ERα, thus attenuating Tamoxifen induced changes on ERα dependent transcription [20]. As a second mechanism, cell surface MUC-1 directly interacts with receptor tyrosine kinases and may also interfere with their downstream pathways [21,22,23]. In line with this, anti-MUC1 antibodies have already been shown to inhibit EGF receptor signaling in cancer cells [10].…”

Erlotinib overcomes paclitaxel-resistant cancer stem cells by blocking the EGFR-CREB/GRβ-IL-6 axis in MUC1-positive cervical cancer

“…We recently reported that erlotinib could enhance the sensitivity of MUC1-expressing cancer cells to paclitaxel 30 . We extended the study by investigating whether paclitaxel-induced CSC enrichment could be affected by erlotinib.…”