MDA-MB-436: Insights on This BRCA1-Deficient Cell Line
Explore key characteristics of the MDA-MB-436 cell line, including its BRCA1 deficiency, molecular markers, culturing methods, and drug response in research.
MDA-MB-436 is a widely studied breast cancer cell line known for its BRCA1 deficiency, making it valuable for research on triple-negative breast cancer and DNA repair mechanisms. Its genetic profile has made it a key model for investigating tumor biology and therapeutic strategies targeting BRCA1-mutant cancers.
Classification And Origin
MDA-MB-436 is classified as a triple-negative breast cancer (TNBC) cell line, lacking estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. It was originally derived from the pleural effusion of a 43-year-old female patient with metastatic breast adenocarcinoma, representing an aggressive, late-stage disease. Gene expression profiling places it within the basal-like TNBC subtype, associated with high proliferative capacity and poor differentiation.
Established at the MD Anderson Cancer Center, MDA-MB-436 was developed as part of broader efforts to create in vitro breast cancer models. It harbors a pathogenic BRCA1 mutation (BRCA1 5396+1G>A), leading to a loss of functional BRCA1 protein and impaired homologous recombination repair (HRR). This mutation distinguishes it from other TNBC models and makes it particularly relevant for studying BRCA1-associated tumorigenesis and therapeutic vulnerabilities.
MDA-MB-436 exhibits mesenchymal-like morphology, with spindle-shaped cells that display high plasticity, a trait linked to increased invasiveness and metastatic potential. It has a slower proliferation rate than other TNBC models, likely due to BRCA1 deficiency and reliance on alternative DNA repair pathways. These characteristics influence its behavior in experimental settings and its utility in preclinical research.
Known BRCA1 Related Features
MDA-MB-436’s BRCA1 deficiency results from the BRCA1 5396+1G>A frameshift mutation, producing a truncated, nonfunctional protein. This severely compromises homologous recombination repair (HRR), forcing reliance on error-prone mechanisms like non-homologous end joining (NHEJ) and microhomology-mediated end joining (MMEJ). The resulting genomic instability accelerates chromosomal rearrangements and mutations, contributing to tumor progression and therapy resistance.
BRCA1 normally stabilizes stalled replication forks, preventing collapse and subsequent DNA damage. Without this function, MDA-MB-436 is highly sensitive to replication stress-inducing agents like hydroxyurea and ATR inhibitors. Studies show increased DNA damage markers, including γ-H2AX and 53BP1 foci, highlighting persistent double-strand breaks and genomic stress, mirroring BRCA1-mutant tumors.
BRCA1 also regulates transcription and chromatin remodeling. MDA-MB-436 exhibits dysregulated expression of epithelial-to-mesenchymal transition (EMT) genes, partly due to the loss of BRCA1-mediated repression of ZEB1 and SNAIL. This results in reduced epithelial markers like E-cadherin and increased mesenchymal markers such as vimentin, reinforcing its invasive nature.
Molecular Markers
MDA-MB-436 lacks ER, PR, and HER2, defining its TNBC classification. It expresses basal-like markers, including high levels of epidermal growth factor receptor (EGFR) and cytokeratins 5/6, common in basal-like TNBC and linked to aggressive tumor behavior.
It also exhibits elevated mesenchymal-associated proteins, reflecting its invasive potential. Vimentin is abundantly expressed, while E-cadherin is reduced, supporting a migratory phenotype. These characteristics align with its ability to model metastatic progression.
Its BRCA1 deficiency influences DNA damage response markers, including elevated 53BP1, which promotes error-prone repair, and persistent γ-H2AX foci, indicating unresolved DNA damage. These markers highlight the genomic instability typical of BRCA1-mutant tumors and explain the cell line’s sensitivity to DNA-damaging agents.
Typical Culturing Methods
MDA-MB-436 requires optimized conditions due to its slower proliferation rate. It thrives in Dulbecco’s Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum (FBS) and 10 μg/mL insulin, which supports metabolic activity and growth.
Cells should be maintained at 37°C in a humidified incubator with 5% CO₂. Passaging is recommended at 70-80% confluence to prevent nutrient depletion and altered behavior. As an adherent cell line, enzymatic detachment using trypsin-EDTA should be performed carefully, limiting exposure to 2-3 minutes to preserve viability.
Drug Response In Experimental Models
MDA-MB-436’s BRCA1 deficiency alters its drug sensitivity, making it particularly susceptible to DNA-damaging agents like platinum-based chemotherapies. It responds well to cisplatin and carboplatin, which induce interstrand crosslinks requiring HRR for repair. In vitro studies show increased apoptosis and reduced clonogenic survival following treatment. However, acquired resistance remains a concern, with mechanisms such as increased drug efflux and secondary mutations in DNA repair pathways contributing to relapse.
It is also a key model for testing poly (ADP-ribose) polymerase (PARP) inhibitors, which exploit synthetic lethality in BRCA1-mutant cells. PARP inhibitors like olaparib and talazoparib prevent single-strand DNA break repair, leading to lethal double-strand breaks in HRR-deficient cells. MDA-MB-436 exhibits significant sensitivity to these inhibitors, showing reduced viability and increased DNA damage markers. However, resistance mechanisms, including BRCA1 reversion mutations and drug efflux transporter upregulation, highlight the need for combination strategies to maintain therapeutic efficacy.