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Published on: November 3, 2023
Intracellular signaling pathways regulate hormone-dependent kallikrein gene expression
Miltiadis Paliouras1, Eleftherios P Diamandis
1Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ont., Canada.
Summary
Androgen stimulation upregulates kallikrein (KLK) genes in breast cancer cells. Key signaling pathways like RAS/MEK/ERK and PI3K/AKT, along with c-MYC, are crucial for this hormone-dependent gene activation.
Area of Science:
- Molecular Biology
- Cancer Research
- Endocrinology
Background:
- Kallikrein (KLK) genes are implicated in various cancers, including breast cancer.
- Hormone-dependent gene regulation is critical in the development and progression of hormone-sensitive breast cancers.
- Understanding the role of signal transduction pathways in KLK gene expression is essential for targeted therapies.
Purpose of the Study:
- To investigate the influence of signal transduction pathways on hormone-dependent kallikrein (KLK) gene expression in androgen-sensitive breast cancer cell lines.
- To identify specific pathways and transcription factors involved in the regulation of KLK genes.
Main Methods:
- Utilized T47D and BT474 breast cancer cell lines.
- Treated cells with steroid hormones and pathway inhibitors (U0126, Wortmannin).
- Quantified KLKs using ELISA; assessed transcript and protein levels via RT-PCR, Western blots, and immunoprecipitations; performed chromatin immunoprecipitations.
Main Results:
- Androgen stimulation upregulated PSA, KLK10, KLK11, KLK13, and KLK14 in T47D cells.
- RAS/MEK/ERK and PI3K/AKT pathways, modulated by U0126 and Wortmannin, were implicated in hormone-dependent KLK gene activation.
- c-MYC expression paralleled KLK expression, and c-MYC binding to KLK promoters (PSA, KLK11) was identified.
Conclusions:
- Hormone-specific upregulation of PSA, KLK10, and KLK11 in T47D cells is dependent on major intracellular signaling pathways.
- This research offers new insights into the regulation of cancer-related KLK genes.
- Identified pathways and transcription factors present potential targets for novel therapeutic strategies in breast cancer.
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