RESEARCH ARTICLE Involvement of multiple cellular pathways in regulating resistance to tamoxifen in BIK-suppressed MCF-7 cells Rubí Viedma-Rodríguez 1,3 & Ruth Ruiz Esparza-Garrido 1,2 & Luis Arturo Baiza-Gutman 3 & Miguel Ángel Velázquez-Flores 1 & Alejandro García-Carrancá 4 & Fabio Salamanca-Gómez 1 & Diego Arenas-Aranda 1 Received: 10 December 2014 /Accepted: 24 March 2015 # International Society of Oncology and BioMarkers (ISOBM) 2015 Abstract Majority of women with estrogen receptor (ER)- positive breast cancers initially respond to hormone therapies such as tamoxifen (TAM; antagonist of estrogen). However, many tumors eventually become resistant to TAM. Therefore, understanding the various cellular components involved in causing resistance to TAM is of paramount importance in designing novel entities for efficacious hormone therapy. Previously, we found that suppression of BIK gene expression induced TAM resistance in MCF-7 breast cancer cells. In or- der to understand the response of these cells to TAM and its association with resistance, a microarray analysis of gene ex- pression was performed in the BIK-suppressed MCF-7 cells and compared it to the TAM-only-treated cells (controls). Several genes participating in various cellular pathways were identified. Molecules identified in the drug resistance pathway were 14-3-3z or YWHAZ, WEE1, PRKACA, NADK, and HSP90AA 1. Further, genes involved in cell cycle control, apoptosis, and cell proliferation were also found differentially expressed in these cells. Transcriptional and translational anal- ysis of key molecules such as STAT2, AKT 3, and 14-3-3z revealed similar changes at the messenger RNA (mRNA) as well as at the protein level. Importantly, there was no cytotoxic effect of TAM on BIK-suppressed MCF-7 cells. Further, these cells were not arrested at the G0-G1 phase of the cell cycle although 30 % of BIK-suppressed cells were arrested at the G2 phase of the cycle on TAM treatment. Furthermore, we found a relevant interaction between 14-3-3z and WEE1, sug- gesting that the cytotoxic effect of TAM was prevented in BIK-suppressed cells because this interaction leads to transi- tory arrest in the G2 phase leading to the repair of damaged DNA and allowing the cells to proliferate. Keywords Breast cancer . Tamoxifen . BIK . Endocrine resistance . Signaling pathways Introduction Antiestrogens such as tamoxifen (TAM) are widely used in the clinic to treat estrogen receptor (ER)-positive breast tumors. About 70 % of all patients with breast cancer overexpress nuclear estrogen receptor alpha (ER-α)[1, 2], rendering it an excellent candidate for endocrine therapy. TAM is an ER antagonist that competitively inhibits the interaction of estro- gen with ER, thus repressing ER activity and is commonly administered as a first-line adjuvant treatment for an ER-α- positive breast tumor [3, 4]. To develop efficacious treatment for TAM-resistant breast cancers, it is important to first understand the complex signal Diego Arenas-Aranda passed away last 2014 (1958–2014). * Rubí Viedma-Rodríguez araceliviedma@hotmail.com 1 Laboratorio de Genómica Funcional y Proteómica, Unidad de Investigación Médica en Genética Humana (UIMGH), Hospital, 06720 México, DF, México 2 Consejo Nacional de Ciencia y Tecnología, Cátedras CONACYT, Av. Insurgentes Sur 1582, Col. Crédito Constructor Del. Benito Juárez C, 03940 México, DF, México 3 Laboratorio de Biología del Desarrollo, Unidad de Morfología y Función, Facultad de Estudios Superiores Iztacala (FES-Iztacala), Universidad Nacional Autónoma de México (UNAM-México), Avenida de los Barrios Número 1, Colonia Los Reyes Iztacala Tlalnepantla, 54090 México, Estado de México, México 4 Subdirección de Investigación Básica, Instituto Nacional de Cancerología (INCan), Av. San Fernando 22, Col. Sección XVI, 14080 México, DF, México Tumor Biol. DOI 10.1007/s13277-015-3374-6