title: Blockade of epidermal growth factor receptors chemosensitizes breast cancer cells through up-regulation of Bnip3L.
abstract: Epidermal growth factor receptor-1 (EGFR) and EGFR-2 (HER2) have become major targets for cancer treatment. Blocking antibodies and small-molecule inhibitors are being used to silence the activity of these receptors in different tumors with varying efficacy. Thus, a better knowledge on the signaling pathways activated by EGFR and HER2 may help unravel novel therapeutic targets and molecular markers of response. Here, we show that treatment of breast cancer cell lines with blocking antibodies against EGFR (cetuximab) or HER2 (trastuzumab) promotes the specific induction of proapoptotic Bnip3L and chemosensitization. Moreover, we found that the Bnip3L gene is transcriptionally activated by FoxO3a. Trastuzumab-mediated induction of Bnip3L and nuclear translocation of FoxO3a was also shown in pleural effusion cells from a breast cancer patient. Transfection of breast cancer cells with constitutively active FoxO3a or with Bnip3L promotes sensitization to chemotherapy-induced apoptosis. On the contrary, blockade of Bnip3L expression by a small interfering RNA strategy significantly diminished the chemosensitizing effect of cetuximab. We found also an inverse correlation between EGFR and Bnip3L expression in surgical specimens from patients with breast cancer. Therefore, blockading EGFR or HER2 specifically up-regulates Bnip3L, which is required for chemosensitization of breast cancer cells. This novel pathway provides also the rationale for therapeutic strategies aimed to induce the expression of Bnip3L.
authors.affiliation: Unidad de Genetica Molecular, Hospital Universitario Marques de Valdecilla, Servicio Cantabro de Salud, Santander, Spain.
authors.forename: Pedro J
authors.initials: PJ
authors.lastname: Real
authors.forename: Adalberto
authors.initials: A
authors.lastname: Benito
authors.forename: Jorge
authors.initials: J
authors.lastname: Cuevas
authors.forename: Maria T
authors.initials: MT
authors.lastname: Berciano
authors.forename: Ana
authors.initials: A
authors.lastname: de Juan
authors.forename: Paul
authors.initials: P
authors.lastname: Coffer
authors.forename: Javier
authors.initials: J
authors.lastname: Gomez-Roman
authors.forename: Miguel
authors.initials: M
authors.lastname: Lafarga
authors.forename: Jose M
authors.initials: JM
authors.lastname: Lopez-Vega
authors.forename: Jose L
authors.initials: JL
authors.lastname: Fernandez-Luna
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D000068818:Cetuximab; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics; D020868:Gene Silencing; D006801:Humans; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D000068878:Trastuzumab; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000068818:Cetuximab; D066246:ErbB Receptors; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; D025521:Tumor Suppressor Proteins; C116838:BNIP3L protein, human; C499517:FOXO3 protein, human