Genetic and epigenetic factors affect RET gene expression in breast cancer cell lines and influence survival in patients.

// Paola Griseri 1 , Ornella Garrone 2 , Alessandra Lo Sardo 1 , Martino Monteverde 3 , Marta Rusmini 1 , Federica Tonissi 3 , Marco Merlano 2 , Paolo Bruzzi 4 , Cristiana Lo Nigro 3, * , Isabella Ceccherini 1, * 1 UOC Medical Genetics, IRCCS Giannina Gaslini Institute, Genoa, Italy 2 Unit of Medical Oncology, Department of Oncology, S. Croce & Carle Teaching Hospital, Cuneo, Italy 3 Laboratory of Cancer Genetics and Translational Oncology, Department of Oncology, S. Croce & Carle Teaching Hospital, Cuneo, Italy 4 Clinical Epidemiology, IRCCS AUO San Martino IST, Genoa, Italy * These authors have contributed equally to this work Correspondence to: Isabella Ceccherini, email: isa.c@unige.it Keywords: RET gene, breast cancer, single nucleotide polymorphism, gene expression, resistance to hormonal therapy Received: July 19, 2015      Accepted: March 04, 2016      Published: March 28, 2016 ABSTRACT Germline and somatic mutations play a crucial role in breast cancer (BC), driving the initiation, progression, response to therapy and outcome of the disease. Hormonal therapy is limited to patients with tumors expressing steroid hormone receptors, such as estrogen receptor (ER), nevertheless resistance often limits its success. The RET gene is known to be involved in neurocristopathies such as Hirschsprung disease and Multiple Endocrine Neoplasia type 2, in the presence of loss-of-function and gain-of-function mutations, respectively. More recently, RET over-expression has emerged as a new player in ER-positive (ER+) BC, and as a potential target to enhance sensitivity and avoid resistance to tamoxifen therapy. Therefore, targeting the RET pathway may lead to new therapies in ER+ BC. To this end, we have investigated the molecular mechanisms which underlie RET overexpression and its possible modulation in two BC cell lines, MCF7 and T47D, showing different RET expression levels. Moreover, we have carried out a pilot association study in 93 ER+ BC patients. Consistent with the adverse role of RET over-expression in BC, increased overall survival was observed in carriers of the variant allele of SNP rs2435357, a RET polymorphism already known to be associated with reduced RET expression.