Novel strategies to target chemoresistant triple-negative breast cancer

Jaganathan Venkatesh,Kaladhar B Reddy,Arun K Rishi

doi:10.18632/genesandcancer.204

Jaganathan Venkatesh, Kaladhar B Reddy + Show 1 more

Open Access

https://doi.org/10.18632/genesandcancer.204

Copy DOI

Abstract

Previous studies from our group and others have shown that current drug treatment(s) strategies eliminate bulk of tumor cells (non-CSCs) but it had a minimal effect on cancer stem cells (CSCs) leading to resistance and tumor recurrence. We studied the effects of CFM-4.16 (CARP-1 functional mimetic) and/or cisplatin on four Triple-negative breast cancer (TNBC) MDA-MB-468, MDA-MB-231, CRL-2335 and BR-1126, two cisplatin resistant CisR/MDA-231 and CisR/MDA-468 and cancer stem cells (CSCs) from resistant cell lines. TNBC cells treated with CFM-4.16 plus cisplatin inhibited the expression of FZD8, LRP6 and c-Myc and significantly enhanced cell death in all the cell lines by ~70%-80% compared with the control(s). When Cisplatin resistant CisR/MDA-231 and CisR/MDA-468 were treated with CFM-4.16 plus cisplatin, they also showed a reduction in FZD8 and LRP6 and increased apoptosis compared to control group. Similarly, CFM-4.16 plus cisplatin treatment reduced mammospheres formation abilities of CSCs by 80-90% compared to control group, increased PARP cleavage and apoptosis. Data shows CFM-4.16 plus cisplatin treatment significantly increased apoptosis/cell death in parental, cisplatin resistant and CSCs. Taken together the data suggests that FZD8-mediated Wnt-signaling plays a major role in mediating CSCs growth and resistance to chemotherapy and its inhibition enhances the chemotherapeutic response in TNBC.

Highlights

Triple-negative breast cancer (TNBC) continues to be a major health problem worldwide despite recent advances in its diagnosis and treatment
These data suggest that CARP-1 functional mimetics (CFMs)-4.16 plus cisplatin treatment had a significant effect in reducing levels of major Wnt-signaling proteins and this leads to enhanced cell death in all the four TNBC cell lines
6B) derived from cisplatin-resistant TNBC cell lines. These data suggest that CFM-4.16 plus cisplatin treatment can reduce Frizzled-8 receptor (FZD8), and LRP in parental, cisplatin resistant and cancer stem cells (CSCs) derived from cis-resistant TNBC cells and increase apoptosis/cell death

Summary

Introduction

Triple-negative breast cancer (TNBC) continues to be a major health problem worldwide despite recent advances in its diagnosis and treatment. Despite the aggressive nature of TNBC, 20% of patients present a pathologic complete response (pCR) after neoadjuvant chemotherapy [3]. The differences in clinical outcomes following neoadjuvant treatment imply that a subset of TNBCs is sensitive to chemotherapy while others become resistant during treatment or are intrinsically less susceptible. In breast cancer, both in vivo and patient data showed a substantial increase in cancer stem cells (CSC) in the residual tumors following treatment with conventional chemotherapy [4, 5]. We postulate inhibition of factors crucial for CSC maintenance such as Wnt-signaling can sensitize TNBC cells to chemotherapy

Methods

Results

Conclusion