Mechanisms of Cisplatin Resistance in Triple Negative Breast Cancer

• Main Author: Pendleton, Christopher Stephen
• Other Authors: Jennifer Pietenpol
• Format: Others
• Language: en
• Published: VANDERBILT 2014
• Subjects: Biochemistry
• Online Access: http://etd.library.vanderbilt.edu/available/etd-11242014-103854/

Genomic instability and deregulated proliferation are hallmarks of human tumors. Cytotoxic chemotherapeutics, including cisplatin, have been used for over forty years to combat cancers that have deregulated proliferation and alterations in DNA damage response pathways. During initial clinical investigation in breast cancer, cisplatin did not prove to be more efficacious when compared to other treatments. However, in the past ten years oncologists identified a patient sub-group that appeared to be exceptional responders to neoadjuvant cisplatin treatment. These new insights may be beneficial to patients with triple negative breast cancer (TNBC). TNBC is defined by the lack of expression of the estrogen receptor, progesterone receptor, and a lack of amplification of the HER2 gene and thus standard of care targeted therapies are ineffective. Historically, cisplatin has proven to be effective against several tumor types but resistance to cisplatin-based therapy is common. With the increase in the use of cisplatin against TNBC in the clinic, we sought to develop cell-line models to identify mechanisms of cisplatin resistance in the basal-like 1 (MDA-MB-468) and basal-like 2 (HCC-1806) subgroups of TNBC. The cisplatin resistant cell line models do not undergo apoptosis in response to cisplatin-induced DNA damage. Caspase-14 was identified as a potential anti-apoptotic mediator in the cisplatin-resistant MDA-MB-468 while an abrogation of the MEK/ERK signaling pathway conferred apoptotic resistance in the cisplatin-resistant HCC-1806 cells. These findings provide insight into identifying signaling pathways involved in drug resistance and eventually potential future biomarkers that may predict clinical response to cisplatin in patients with TNBC.