IDENTIFICATION AND FUNCTIONAL PROFILING OF ERA-INTERACTING LNCRNAS AS NOVEL PUTATIVE MOLECULAR TARGETS FOR BREAST CANCER TREATMENT

BC IS THE MOST FREQUENTLY DIAGNOSED MALIGNANCY AMONG WOMEN WORLWIDE AND REMAINS A LEADING CAUSE OF CANCER-RELATED DEATH. THE MAJORITY OF BREAST TUMORS ARE HORMONE-RESPONSIVE, BASED ON THE EXPESSION OF HORMONE RECEPTORS. AMONG OTHERS, ERΑ IS CONSIDERED THE MAIN VEHICLE OF OF ESTROGEN-MEIDATED PRO-TUMORAL AND MITOGENIC EFFECTS ON BREAST CANCER DEVELOPMENT. ENDOCRINE THERAPY REPRESENTS THE MAIN STRATEGY FOR THE TREATMENT OF ERΑ-POSITIVE BREAST CANCERS. HOWEVER, THE FREQUENT ONSET OF INTRINSIC OR ACQUIRED RESISTANCE SEVERELY LIMITS ITS LONG-TERM EFFICACY. RECENT EVIDENCE REVEALED THE ROLE OF ERΑ AS AN RNA-BINDING PROTEIN (RBP), DISPLAYING NEW POTENTIAL AVENUES FOR THE IDENTIFICATION OF NON-CANONICAL REGULATORS OF ERΑ ONCOGENIC FUNCTIONS. IN THIS CONTEXT, THE PRESENT STUDY INVESTIGATED A SPECIFIC SUBSET OF ERΑ-INTERACTING LONG NON-CODING RNAS (LNCRNAS) AS POTENTIAL MODULATORS OF HORMONE-RESPONSIVE BC BIOLOGY AND THEIR PUTATIVE ROLE AS THERAPEUTIC TARGETS. ERΑ-ASSOCIATED LNCRNAS WERE IDENTIFIED THROUGH RNA-IMMUNOPRECIPITATION COUPLED WITH NEXT-GENERATION SEQUENCING (NGS), FOLLOWED BY FUNCTIONAL CHARACTERIZATION OF FITNESS LNCRNAS. THEIR CONTRIBUTION TO KEY BC HALLMARKS INCLUDING PROLIFERATION, MIGRATION, CHROMATIN DYNAMICS, ESTROGENIC SIGNALING AND APOPTOSIS WAS ASSESSED USING ANTISENSE OLIGONUCLEOTIDE (ASO)-MEDIATED GENE SILENCING IN DIFFERENT BC MODELS. AMONG THE MOST PROMISING CANDIDATES, PVT1, FGD5-AS1 AND EPB41L4A-AS1 DISPLAYED A ROBUST INTERACTION WITH ERΑ AND WERE SELECTED FOR FURTHER INVESTIGATIONS. PARTICULARLY, INTEGRATIVE MULTI-OMICS ANALYSES PERFORMED UPON PVT1 DEPLETION PROVIDED FURTHER INSIGHT INTO ITS FUNCTIONAL EFFECT ON GENE EXPRESSION, MODULATION OF MULTI-MOLECULAR REGULATORY NETWORKS AND CHROMATIN ARCHITECTURE DYNAMICS IN BC. OVERALL, THE OBTAINED RESULTS DEMONSTRATE THAT ERΑ-INTERACTING LNCRNAS REPRESENT KEY COMPONENTS OF ERΑ-REGULATORY MACHINERY, ACTIVELY MODULATING ITS ONCOGENIC ACTIVITY AND UNVEIL NOVEL DRUGGABLE VULNERABILITIES THAT MAY CONTRIBUTE TO OVERCOME RESISTANCE TO HORMONE THERAPIES IN BREAST CANCER.