Tumor Suppressor Mir-16 Mediates ErbB-2-Targeted Therapies Effects in Breast and Gastric Cancer

VENTURUTTI L, CORDO RUSSO RI, RIVAS MA, MERCOGLIANO F, IZZO F, DE MARTINO M, OAKLEY RH, YANKILEVICH P, ALLEMAND D, CHARREAU EH, CIDLOWSKI JA, SCHILLACI R, ELIZALDE PV

Boston, Massachusetts, USA

Congreso; 98th Annual Meeting of the Endocrine Society; 2016

Overexpression of ErbB-2, a member of the ErbBsfamily of receptor tyrosine kinases, accounts for a clinically aggressivebreast cancer (BC) subtype (ErbB-2 positive). Trastuzumab (TZ), an anti-ErbB-2monoclonal antibody, is the most commonly used therapeutic option forErbB-2-positive BC. However, many patients show de novo oracquired resistance. Lapatinib (L), a reversible inhibitor of ErbB-2 and EGFRtyrosine kinases, provides clinical benefit to a subset of patients progressingon TZ, but less than 25% achieve an objective response and the majority eventuallydevelops L resistance. On the other hand, miRNAs (miRs) are short non-codingendogenous RNAs with regulatory functions and a key role in cancer. Wepreviously reported that miR-16 is upregulated by TZ in TZ-sensitive, but notin resistant BC models. Our molecular mechanisms studies revealed that this ismediated by ErbB-2 downstream signaling pathways and the oncogene c-Myc, whichinhibit miR-16 expression. We also disclosed a novel role for miR-16 as a tumorsuppressor and showed that miR-16 overexpression could serve as an alternativetherapeutic strategy for ErbB-2 positive BC. Lastly, we identified two novelmiR-16 targets, CCNJ and FUBP1, whose downregulation underlies miR-16anti-proliferative effects. Here, our first aim was to explore miR-16 role on Ltherapeutic effects in ErbB-2 positive BC. In line with our observations withTZ, we found that L induced miR-16 upregulation only in L sensitive cells,where L suppressed cell growth, inhibited ErbB-2 downstream signaling, c-Mycexpression and miR-16 targets levels. In resistant cell lines, L was unable toalter the expression of c-Myc, miR-16 or its direct targets. Interestingly, Ldid enhance miR-16 levels in L-sensitive cells with intrinsic or acquired TZresistance. MiR-16 overexpression inhibited proliferation of both L-sensitiveand resistant BC cells, supporting its role as potent tumor suppressor. Oursecond aim was to extend our observations in BC to gastric cancer (GC), anothercancer type with ErbB-2 overexpression, in which TZ is used in the metastaticsetting. In line with our results in BC, we found that TZ induced miR-16upregulation only in TZ-sensitive GC models. In these cells, TZ treatmentinhibited the Phosphatidylinositol 3-phosphate and p42/p44mitogen-activated kinases pathways, downregulated c-Myc, and reduced CCNJ andFUBP1 expression. On the contrary, TZ failed to alter signaling pathwaysactivation or CCNJ and FUBP1 levels in resistant cells. Importantly, miR-16forced expression successfully inhibited proliferation of both TZ-sensitive and-resistant ErbB-2 positive GC cells. Our results shed light on miR-16 role onthe mechanisms of action and resistance to ErbB-2-targeted therapies in BC andGC, and provide a mechanistic insight into the benefit from L treatment seen inBC patients with TZ-refractory disease.