title: Expression of mitochondrial regulators PGC1α and TFAM as putative markers of subtype and chemoresistance in epithelial ovarian carcinoma.
abstract: Epithelial ovarian carcinoma (EOC), the major cause of gynaecological cancer death, is a heterogeneous disease classified into five subtypes. Each subtype has distinct clinical characteristics and is associated with different genetic risk factors and molecular events, but all are treated with surgery and platinum/taxane regimes. Tumour progression and chemoresistance is generally associated with major metabolic alterations, notably altered mitochondrial function(s). Here, we report for the first time that the expression of the mitochondrial regulators PGC1α and TFAM varies between EOC subtypes; furthermore, we have identified a profile in clear-cell carcinoma consisting of undetectability of PGC1α/TFAM, and low ERα/Ki-67. By contrast, high-grade serous carcinomas were characterised by a converse state of PGC1α/TFAM, ERα positivity and a high Ki-67 index. Interestingly, loss of PGC1α/TFAM and ERα was found also in a non-clear cell EOC cell line made highly resistant to platinum in vitro. Similar to clear-cell carcinomas, these resistant cells also showed accumulation of glycogen. Altogether, our data provide mechanistic insights into the chemoresistant nature of ovarian clear-cell carcinomas. Furthermore, these findings corroborate the need to take into account the diversity of EOC and to develop subtype specific treatment strategies.
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska CCK, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Marike
authors.initials: M
authors.lastname: Gabrielson
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska CCK, Karolinska Institutet, Stockholm, Sweden.
authors.forename: My
authors.initials: M
authors.lastname: Björklund
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska CCK, Karolinska Institutet, Stockholm, Sweden; Department of Pathology-Cytology, Radiumhemmet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Joseph
authors.initials: J
authors.lastname: Carlson
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska CCK, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Shoshan
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006003:Glycogen / Q000378:metabolism; D006801:Humans; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011379:Prognosis; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D024101:Mitochondrial Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C499631:TFAM protein, human; D014157:Transcription Factors; D006003:Glycogen