Abstract 5437: miR-302b as adjuvant therapeutic tool to improve chemotherapy efficacy in human triple-negative breast cancer

• Published in: Cancer research (Chicago, Ill.) Ill.), 2017-07, Vol.77 (13_Supplement), p.5437-5437
• Main Authors: Cataldo, Alessandra, Plantamura, Ilaria, D'Ippolito, Elvira, Romero-Cordoba, Sandra, Baroni, Sara, Cancilia, Valeria, Tripodo, Claudio, Palmieri, Dario, Iorio, Marilena V.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2017-5437

Introduction: Triple-negative breast cancer (TNBC) accounts for 15-20% of all breast cancer cases, with the worst outcome of all subtypes. For TNBC, still lacking targeted therapies, the only therapeutic option is currently chemotherapy, and despite a good initial response, patients often develop drug resistance. MiRNAs can modulate chemoresistance by affecting DNA repair, cell cycle progression, apoptosis and also tumor microenvironment. Macrophages constitute a major component of the immune microenvironment of cancer and pro-tumor M2 macrophages have been associated with resistance to chemotherapeutic treatments. Our previous data showed that miR-302b over-expression enhances sensitivity to cisplatin in breast cancer cell lines by targeting directly E2F1 and indirectly ATM. Here, we investigated the potential of miR-302b as a therapeutic tool to enhance cisplatin response in a TNBC mouse model and which pathways are involved in this mechanism both in tumor cells and microenvironment. Moreover, miR-302b prognostic value was assessed in a cohort of TNBC patients with available clinical outcome . Finally, we evaluated if miR-302b enhances the sensitivity to doxorubicin, another chemotherapeutic agent used as first-line therapy in TNBC patients. Material and method: MDA-MB-231 TNBC cells were injected into the mammary fat pad of female SCID mice and then treated with lipid nanoparticles containing miR-302b or cel-miR-67 control, alone or in combination with cisplatin. Gene expression profile on collected tumors was performed by microarray and tumor sections were stained with anti-arginase 1 (M2 marker) to evaluate the number of M2 macrophages. MiR-302b expression was assessed in 39 TNBC treated with chemotherapy in adjuvant setting, and associated with prognosis. Finally, MDA-MB-231 cells were transfected with miR-302b precursor or control treated with doxorubicin for 24h and then assessed for cell viability. Results: Our results show that miR-302b combination with cisplatin significantly impaired tumor growth in comparison with cel-67 control and cisplatin (p= 0.03), and reduced the number of M2 macrophages in the tumor microenvironment (p=0.005). Moreover, gene expression profile of collected tumors confirm immune system modulation. Notably, miR-302b expression was associated with disease-free survival and overall survival in TNBC patients treated with adjuvant chemotherapy. Furthermore, we found that miR-302b also enhances sensitivity to doxorubicin in vi