title: Involvement of multiple cellular pathways in regulating resistance to tamoxifen in BIK-suppressed MCF-7 cells.
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 order to understand the response of these cells to TAM and its association with resistance, a microarray analysis of gene expression 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 analysis 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, suggesting that the cytotoxic effect of TAM was prevented in BIK-suppressed cells because this interaction leads to transitory arrest in the G2 phase leading to the repair of damaged DNA and allowing the cells to proliferate.
authors: Laboratorio de Genómica Funcional y Proteómica, Unidad de Investigación Médica en Genética Humana (UIMGH), Hospital, 06720, México, DF, México. araceliviedma@hotmail.com.|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. araceliviedma@hotmail.com.
authors: Rubí
authors: R
authors: Viedma-Rodríguez
authors: Laboratorio de Genómica Funcional y Proteómica, Unidad de Investigación Médica en Genética Humana (UIMGH), Hospital, 06720, México, DF, México.|Consejo Nacional de Ciencia y Tecnología, Cátedras CONACYT, Av. Insurgentes Sur 1582, Col. Crédito Constructor Del. Benito Juárez C, 03940, México, DF, México.
authors: Ruth
authors: R
authors: Ruiz Esparza-Garrido
authors: 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.
authors: Luis Arturo
authors: LA
authors: Baiza-Gutman
authors: Laboratorio de Genómica Funcional y Proteómica, Unidad de Investigación Médica en Genética Humana (UIMGH), Hospital, 06720, México, DF, México.
authors: Miguel Ángel
authors: MÁ
authors: Velázquez-Flores
authors: Subdirección de Investigación Básica, Instituto Nacional de Cancerología (INCan), Av. San Fernando 22, Col. Sección XVI, 14080, México, DF, México.
authors: Alejandro
authors: A
authors: García-Carrancá
authors: Laboratorio de Genómica Funcional y Proteómica, Unidad de Investigación Médica en Genética Humana (UIMGH), Hospital, 06720, México, DF, México.
authors: Fabio
authors: F
authors: Salamanca-Gómez
authors: Laboratorio de Genómica Funcional y Proteómica, Unidad de Investigación Médica en Genética Humana (UIMGH), Hospital, 06720, México, DF, México.
authors: Diego
authors: D
authors: Arenas-Aranda
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis* / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004967:Estrogens / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D024101:Mitochondrial Proteins; D009363:Neoplasm Proteins / Q000096:biosynthesis; D013629:Tamoxifen / Q000008:administration & dosage*
chemical_list: D048948:14-3-3 Proteins; D051017:Apoptosis Regulatory Proteins; C096820:BIK protein, human; D004967:Estrogens; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D009363:Neoplasm Proteins; D013629:Tamoxifen
keywords: BIK; Breast cancer; Endocrine resistance; Signaling pathways; Tamoxifen