title: Restraining FOXO3-dependent transcriptional BMF activation underpins tumour growth and metastasis of E-cadherin-negative breast cancer.
abstract: Loss of cellular adhesion leads to the progression of breast cancer through acquisition of anchorage independence, also known as resistance to anoikis. Although inactivation of E-cadherin is essential for acquisition of anoikis resistance, it has remained unclear how metastatic breast cancer cells counterbalance the induction of apoptosis without E-cadherin-dependent cellular adhesion. We report here that E-cadherin inactivation in breast cancer cells induces PI3K/AKT-dependent FOXO3 inhibition and identify FOXO3 as a novel and direct transcriptional activator of the pro-apoptotic protein BMF. As a result, E-cadherin-negative breast fail to upregulate BMF upon transfer to anchorage independence, leading to anoikis resistance. Conversely, expression of BMF in E-cadherin-negative metastatic breast cancer cells is sufficient to inhibit tumour growth and dissemination in mice. In conclusion, we have identified repression of BMF as a major cue that underpins anoikis resistance and tumour dissemination in E-cadherin-deficient metastatic breast cancer.
authors.affiliation: Department of Molecular Cancer Research, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Hornsveld
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Tenhagen
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: R A
authors.initials: RA
authors.lastname: van de Ven
authors.affiliation: Department of Molecular Cancer Research, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: A M M
authors.initials: AM
authors.lastname: Smits
authors.affiliation: Department of Molecular Cancer Research, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: M H
authors.initials: MH
authors.lastname: van Triest
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: van Amersfoort
authors.affiliation: Department of Molecular Cancer Research, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: D E A
authors.initials: DE
authors.lastname: Kloet
authors.affiliation: Department of Molecular Cancer Research, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: T B
authors.initials: TB
authors.lastname: Dansen
authors.affiliation: Department of Molecular Cancer Research, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: B M
authors.initials: BM
authors.lastname: Burgering
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: P W B
authors.initials: PW
authors.lastname: Derksen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D023102:Anoikis / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects; D000072224:Bcl-2-Like Protein 11 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004318:Doxycycline / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D000071316:Forkhead Box Protein O3 / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary; D061986:MCF-7 Cells; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D015533:Transcriptional Activation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000072224:Bcl-2-Like Protein 11; C435486:Bmf protein, mouse; D015820:Cadherins; D000071316:Forkhead Box Protein O3; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D004318:Doxycycline