Differential Response to All-Trans Retinoic Acid in Breast Cancer Cells: Effects on Metastatic Pathways and Gene Expression

VANDERHOEVEN FIORELLA; MONDACA JOSELINA MAGALÍ; REDONDO ANALIA L; SANCHEZ ANGEL MATIAS; FLAMINI MARINA INÉS

Buenos Aires

Simposio; BUENOS AIRES BREAST CANCER SYMPOSIUM - 2024; 2024

Breast cancer (BC) is women's most frequent malignant neoplasia and has a high mortality rate. All-trans retinoic acid(RA), a vitamin A-derived pleiotropic signaling molecule, regulates critical genetic programs and shows promise fortreating various neoplasias, including BC. However, its use in solid tumors is limited. Previous studies have shown thatsensitivity to RA varies among BC cells. We aimed to determine RA’s effects on metastatic processes and characterizethe expression profiles of target genes using the Gene Expression Omnibus (GEO) public repository and assess itsimpact on cell viability in different BC cell lines. We performed Gene Ontology (GO), Kyoto Encyclopedia of Genes andGenomes (KEGG), and Differential Gene Expression (DGE) analysis, using the GSE103426 database. In-vitro MTTassays and RT-q-PCR experiments were conducted to evaluate the effect of RA on cell viability. Our GO analysisrevealed that RA regulates biological processes such as cell migration, motility, epithelial cell differentiation, epithelialmesenchymal transition, and apoptosis in MDA-MB-231 cells. KEGG analysis indicated that RA downregulates pathwaysinvolving differentiation, inflammation, proliferation, angiogenesis, and inhibitory pathways of apoptosis, invasion,migration, and metastasis. Through DGE, we demonstrated that RA modulated the expression of SRC, PTK2, VIM, andCTTN, validated by RT-q-PCR. We confirmed the absence of retinoic acid receptors (RARs) and the reduced ability ofRA to inhibit MDA-MB-231 cell viability, indicating resistance to RA. Conversely, the viability of T-47D cells decreased atlower RA doses. In conclusion, despite the absence of RARs, RA affects and modulates mRNA levels in RA-resistantcells, downregulating pathways involved in metastatic processes. These results suggest RA could be significant as apotential therapy for metastatic breast cancers lacking specific treatment options.