Bcl-2 Up-Regulation Mediates Taxane Resistance Downstream of APC Loss.
Angelique R WiseSara MaloneyAdam HeringSarah ZabalaGrace E RichmondMonica K VanKlompenbergMurlidharan T NairJenifer R ProsperiPublished in: International journal of molecular sciences (2024)
Triple-negative breast cancer (TNBC) patients are treated with traditional chemotherapy, such as the taxane class of drugs. One such drug, paclitaxel (PTX), can be effective in treating TNBC; however, many tumors will develop drug resistance, which can lead to recurrence. In order to improve patient outcomes and survival, there lies a critical need to understand the mechanism behind drug resistance. Our lab made the novel observation that decreased expression of the Adenomatous Polyposis Coli (APC) tumor suppressor using shRNA caused PTX resistance in the human TNBC cell line MDA-MB-157. In cells lacking APC, induction of apoptosis by PTX was decreased, which was measured through cleaved caspase 3 and annexin/PI staining. The current study demonstrates that CRISPR-mediated APC knockout in two other TNBC lines, MDA-MB-231 and SUM159, leads to PTX resistance. In addition, the cellular consequences and molecular mechanisms behind APC-mediated PTX response have been investigated through analysis of the BCL-2 family of proteins. We found a significant increase in the tumor-initiating cell population and increased expression of the pro-survival family member Bcl-2, which is widely known for its oncogenic behavior. ABT-199 (Venetoclax), is a BH3 mimetic that specifically targets Bcl-2. ABT-199 has been used as a single or combination therapy in multiple hematologic malignancies and has shown promise in multiple subtypes of breast cancer. To address the hypothesis that APC-induced Bcl-2 increase is responsible for PTX resistance, we combined treatment of PTX and ABT-199. This combination treatment of CRISPR-mediated APC knockout MDA-MB-231 cells resulted in alterations in apoptosis, suggesting that Bcl-2 inhibition restores PTX sensitivity in APC knockout breast cancer cells. Our studies are the first to show that Bcl-2 functional inhibition restores PTX sensitivity in APC mutant breast cancer cells. These studies are critical to advance better treatment regimens in patients with TNBC.
Keyphrases
- cell cycle arrest
- breast cancer cells
- combination therapy
- cell death
- induced apoptosis
- endoplasmic reticulum stress
- pi k akt
- oxidative stress
- poor prognosis
- end stage renal disease
- escherichia coli
- endothelial cells
- gene expression
- crispr cas
- squamous cell carcinoma
- single cell
- prognostic factors
- ejection fraction
- chronic kidney disease
- emergency department
- mesenchymal stem cells
- cell therapy
- drug induced
- long non coding rna
- genome editing
- cell proliferation
- peritoneal dialysis
- dna methylation
- diabetic rats
- locally advanced
- patient reported outcomes
- radiation therapy
- high resolution