title: Expression of the forkhead transcription factor FOXL2 correlates with good prognosis in breast cancer patients treated with tamoxifen.
abstract: Aromatase is an important enzyme in the local synthesis of oestrogens and its expression has been shown to be increased in breast cancer through the activation of multiple promoters. However, the mechanisms behind this are not yet fully understood. A novel candidate in this context is the transcription factor forkhead box L2 (FOXL2), which has been recognised to be co-expressed with aromatase and transcriptionally active promoter II in developing goat and chicken ovaries. We propose that FOXL2 could be involved in the increased expression of aromatase in breast cancer. We examined FOXL2 and its relation to aromatase in 132 post-menopausal breast cancer patients by immunohistochemistry. Using in silico analysis, we further searched for FOXL2 binding-elements in the aromatase gene promoters. The results demonstrate that FOXL2 is expressed in breast cancer and influences clinical outcome with improved recurrence-free survival in cases with nuclear expression. In a multivariate Cox model, nuclear FOXL2 was a significant prognostic factor in ER-positive patients treated with tamoxifen (HR=0.18, 95% confidence interval (CI)=0.04-0.81, P=0.03). Tumours expressing nuclear FOXL2 were also more likely positive for stromal and/or cytoplasmic aromatase (P=0.03 and P=0.008, respectively). In silico analyses revealed binding elements of FOXL2 in promoters I.3, II and I.7 of the aromatase gene of which promoter I.7 was most significant. In conclusion, this is the first study to report that FOXL2 is expressed in breast cancer and correlates with aromatase as well as with clinical outcome. The results further strengthen a possible binding of FOXL2 to aromatase promoter I.7. Nevertheless, whether FOXL2 is a direct activator of aromatase requires further investigation.
authors.affiliation: Department of Clinical Medicine, School of Health and Medical Sciences, Örebro University, 701 85 Örebro, Sweden. pia.wegman@oru.se
authors.forename: Pia
authors.initials: P
authors.lastname: Wegman
authors.forename: Anna
authors.initials: A
authors.lastname: Göthlin Eremo
authors.forename: Angelica
authors.initials: A
authors.lastname: Lindlöf
authors.forename: Mats
authors.initials: M
authors.lastname: Karlsson
authors.forename: Olle
authors.initials: O
authors.lastname: Stål
authors.forename: Sten
authors.initials: S
authors.lastname: Wingren
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001141:Aromatase / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D005260:Female; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D053208:Kaplan-Meier Estimate; D011379:Prognosis; D011401:Promoter Regions, Genetic; D013629:Tamoxifen / Q000627:therapeutic use*; D047368:Tumor Burden
chemical_list: D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; C421604:FOXL2 protein, human; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors; D013629:Tamoxifen; D001141:Aromatase; D019363:Cytochrome P-450 CYP1A1