Genes & Cancer

Novel strategies to target chemoresistant triple-negative breast cancer

Jaganathan Venkatesh1,2, Arun K. Rishi1,2,3 and Kaladhar B. Reddy3,4

1 John D. Dingell VA Medical Center, Wayne State University, Detroit, MI, USA

2 Department of Oncology, Wayne State University, Detroit, MI, USA

3 Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA

4 Department of Pathology, Wayne State University, Detroit, MI, USA


Kaladhar B. Reddy, email:

Keywords: Cell cycle and apoptosis regulator 1 (CARP-1), cancer stem cells, CFM-4.16, apoptosis, triple-negative breast cancer

Received: May 23, 2020 Accepted: July 17, 2020 Published: July 22, 2020


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.

PII: 204