MICRORNA EXPRESSION PROFILE OF TRIPLE NEGATIVE BREAST CANCER IN HUMAN TISSUE AND MURINE MODELS AND THEIR REGULATION BY METABOLIC SYNDROME

VERA SANCHEZ L; FARRÉ PL; DUCA RB; GRAÑA K; SCALISE G; DALTON GN; MASSILLO C; MORO J; LACUNZA E; PICCIONI F; CAMPO VERDE ARBOCCO F; DE SIERVI A; DE LUCA P

MAR DEL PLATA

Congreso; 67 Reunión Anual SAIC; 2022

Triple negative breast cancer (TNBC) is the breast cancer (BC) subtype with worst prognosis and fewest therapeutic options. Metabolic syndrome (MS) is a risk factor for BC and its prevalence is higher in TNBC. Previously, we identified several miRNAs that could explain MS and BC link. Thus, we identified to let-7b-5p, miR-28-3p and -877-5p as miRNAs altered in plasma from women with AASM that are also dysregulated in BC tissue. The aim of this work was to identify miRNAs key in the TNBC development associated with MS in human samples and to validate the expression of these miRNAs candidates in murine models of TNBC and MS. Our hypothesis is that miRNAs whose expression is altered in TNBC could explain the high aggressiveness of this molecular subtype and its association to MS.We found 222 miRNAs exclusively altered in TNBC tumors compared to normal adjacent tissue by bioinformatic analysis of GDC TCGA Breast Cancer patient database. We selected miR-19b-2, -135b, -29c and -138-1 for further analysis since, according to a bibliographic search, they have functions linked to AASM. We determined their impact on patient survival from TCGA BRCA dataset using UCSC Xena tool. Interestingly, miR-877-5p expression correlates with low BC patient survival while miR29c-5p and -3p increase survival and progression-free interval of TNBC patients.We validated these results in two murine models of TNBC and MS by determining the expression of these miRNAs in normal mammary tissue (MT) and tumors derived from 4T1 and MDA-MB-231 cells generated in mice with AASM or control. Expression of miR-19b-3p was increased in 4T1 tumors compared to MT while miR-29c-5p and let-7b-5p were diminished. Moreover, miR-877-5p and -28-3p were increased in MDA-MB-231 xenografts from AASM mice compared to control. Our results suggest that miR-19b-3p, -29c-5p and let-7b-5p could be specific therapeutic targets for TNBC while miR-877-5p emerges as a molecular target for TNBC associated to MS.