Development of CAPER peptides for the treatment of triple negative breast cancer
Shannon D Chilewski1, Devyani Bhosale1, Sundee Dees1
1Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of the Sciences, Philadelphia, PA, USA.
Abstract:
Triple negative breast cancer (TNBC) is a heterogeneous disease, which lacks expression of the estrogen receptor (ER), progesterone receptor (PR) and the human epidermal growth factor 2 receptor (HER2). This subtype of breast cancer has the poorest prognosis with limited therapies currently available, and hence additional options are needed. CAPER is a coactivator of the activator protein-1 (AP-1) (interacting specifically with the c-Jun component) and the ER and is known to be involved in human breast cancer pathogenesis. Recent published data have demonstrated a role for CAPER in TNBC and, as such, disrupting the function of CAPER with c-Jun could be a novel approach to treat TNBC patients. The data presented here shows the development and in vitro testing of CAPER-derived peptides that inhibit the coactivator activity of CAPER with c-Jun. These CAPER peptides result in a decrease in cell number and an increase in apoptosis in two TNBC cell lines, MDA-MB-231 and BT-549, while having no effect on the non-tumorigenic cell line MCF 10A. Additionally, two modes of action were demonstrated which appear to be cell line dependent: 1) a modulation of phosphorylated c-Jun leading to a decrease in Bcl-2 in MDA-MB-231 cells and a decrease in p21 in BT-549 cells and 2) a decrease in DNA repair proteins, leading to impaired DNA repair function in MDA-MB-231 cells. The data presented here supports further development of CAPER-derived peptides for the treatment of TNBC.
Insights
Novel CAPER-derived peptides show promise for treating triple-negative breast cancer (TNBC). These peptides inhibit CAPER
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Triple-negative breast cancer (TNBC) lacks ER, PR, and HER2 expression, presenting a poor prognosis and limited treatment options.
- CAPER, a coactivator of AP-1 (c-Jun) and ER, plays a role in breast cancer pathogenesis.
- Disrupting CAPER-c-Jun interaction is a potential therapeutic strategy for TNBC.
Purpose of the Study:
- To develop and test CAPER-derived peptides that inhibit CAPER's coactivator activity with c-Jun.
- To evaluate the efficacy of these peptides against TNBC cell lines.
- To elucidate the mechanisms of action for CAPER-derived peptide treatment.
Main Methods:
- Development of CAPER-derived peptides designed to inhibit CAPER-c-Jun interaction.
- In vitro testing of peptide efficacy on TNBC cell lines (MDA-MB-231, BT-549) and a non-tumorigenic cell line (MCF 10A).
- Analysis of cellular responses including cell number, apoptosis, and molecular pathways (c-Jun phosphorylation, Bcl-2, p21, DNA repair proteins).
Main Results:
- CAPER-derived peptides reduced cell number and increased apoptosis in TNBC cell lines MDA-MB-231 and BT-549.
- No significant effects were observed in the non-tumorigenic MCF 10A cell line.
- Mechanisms included modulation of phosphorylated c-Jun, affecting Bcl-2 and p21 levels, and impaired DNA repair in MDA-MB-231 cells.
Conclusions:
- CAPER-derived peptides demonstrate anti-cancer activity against TNBC cell lines in vitro.
- The observed effects are specific to TNBC cells, suggesting targeted therapeutic potential.
- Further development of CAPER-derived peptides is warranted for TNBC treatment.
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