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MUC1-C oncoprotein promotes STAT3 activation in an autoinductive regulatory loop
Rehan Ahmad1, Hasan Rajabi, Michio Kosugi
1Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Science Signaling
|February 18, 2011
Summary
Mucin 1 (MUC1) carboxyl-terminal subunit (MUC1-C) activates Signal transducer and activator of transcription 3 (STAT3) in breast cancer. This MUC1-C and STAT3 interaction forms an autoinductive loop promoting cancer cell survival.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- Signal transducer and activator of transcription 3 (STAT3) is frequently activated in various human cancers, including breast cancer.
- Mucin 1 (MUC1), a cell surface glycoprotein overexpressed in carcinomas, promotes cancer cell survival and transformation, similar to STAT3.
- MUC1 exists as a heterodimeric complex, with the MUC1 carboxyl-terminal subunit (MUC1-C) playing a key role in cellular signaling.
Purpose of the Study:
- To investigate the molecular interaction between MUC1-C and the JAK1-STAT3 signaling pathway in breast cancer cells.
- To elucidate the role of MUC1-C in STAT3 activation and its contribution to MUC1 gene transcription.
- To evaluate the therapeutic potential of targeting the MUC1-C interaction with STAT3 using the inhibitor GO-201.
Main Methods:
- Co-immunoprecipitation assays to assess the association between MUC1-C, JAK1, and STAT3.
- Western blotting to detect protein levels and STAT3 activation.
- Chromatin immunoprecipitation to determine promoter occupancy of MUC1-C and STAT3.
- Quantitative PCR to measure MUC1 gene expression.
- Treatment with the MUC1-C inhibitor GO-201 to assess its effects on signaling pathways and gene expression.
Main Results:
- MUC1-C directly interacts with Janus-activated kinase 1 (JAK1) and STAT3 within the gp130-JAK1-STAT3 complex in breast cancer cells.
- MUC1-C is essential for JAK1-mediated activation of STAT3.
- MUC1-C and activated STAT3 bind to the MUC1 promoter, indicating MUC1-C's role in STAT3-mediated MUC1 transcription.
- The inhibitor GO-201 disrupts the MUC1-C interaction with STAT3, reducing promoter occupancy and STAT3 target gene activation, including MUC1 itself.
Conclusions:
- MUC1-C actively promotes STAT3 activation in breast cancer.
- MUC1-C and STAT3 form an autoinductive feedback loop, enhancing MUC1 expression and contributing to cancer cell survival.
- Targeting the MUC1-C-STAT3 interaction with inhibitors like GO-201 represents a potential therapeutic strategy for MUC1- and STAT3-driven malignancies.
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