title: BDNF is associated with SFRP1 expression in luminal and basal-like breast cancer cell lines and primary breast cancer tissues: a novel role in tumor suppression?
abstract: Secreted frizzled related protein 1 (SFRP1) functions as an important inhibitor of the Wnt pathway and is a known tumor suppressor gene, which is epigenetically silenced in a variety of tumors e.g. in breast cancer. However, it is still unclear how SFRP1 exactly affects the Wnt pathway. Our aim was to decipher SFRP1 involvement in biochemical signaling in dependency of different breast cancer subtypes and to identify novel SFRP1-regulated genes. We generated SFRP1 over-expressing in vitro breast cancer models, reflecting the two major subtypes by using basal-like BT20 and luminal-like HER2-positive SKBR3 cells. DNA microarray expression profiling of these models revealed that SFRP1 expression potentially modulates Bone morphogenetic protein- and Smoothened signaling (p<0.01), in addition to the known impact on Wnt signaling. Importantly, further statistical analysis revealed that in dependency of the cancer subtype model SFRP1 may affect the canonical and non-canonical Wnt pathway (p<0.01), respectively. While SFRP1 re-expression generally mediated distinct patterns of transcriptionally induced or repressed genes in BT20 and SKBR3 cells, brain derived neurotrophic factor (BDNF) was identified as a SFRP1 induced gene in both cell lines. Although BDNF has been postulated as a putative oncogene, the co-regulation with SFRP1 indicates a potential suppressive function in breast cancer. Indeed, a positive correlation between SFRP1 and BDNF protein expression could be shown (p<0.001) in primary breast cancer samples. Moreover, TCGA dataset based analysis clearly underscores that BDNF mRNA is down-regulated in primary breast cancer samples predicting a poor prognosis of these patients. In line, we functionally provide evidence that stable BDNF re-expression in basal-like BT20 breast cancer cells blocks tumor cell proliferation. Hence, our results suggest that BDNF might rather mediate suppressive than promoting function in human breast cancer whose mode of action should be addressed in future studies.
authors.affiliation: Molecular Oncology Group, Institute of Pathology, Medical Faculty of the RWTH Aachen University, Aachen, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Huth
authors.affiliation: Molecular Oncology Group, Institute of Pathology, Medical Faculty of the RWTH Aachen University, Aachen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Rose
authors.affiliation: Molecular Oncology Group, Institute of Pathology, Medical Faculty of the RWTH Aachen University, Aachen, Germany.
authors.forename: Veronika
authors.initials: V
authors.lastname: Kloubert
authors.affiliation: Molecular Oncology Group, Institute of Pathology, Medical Faculty of the RWTH Aachen University, Aachen, Germany.
authors.forename: Wiebke
authors.initials: W
authors.lastname: Winkens
authors.affiliation: Molecular Oncology Group, Institute of Pathology, Medical Faculty of the RWTH Aachen University, Aachen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schlensog
authors.affiliation: Institute of Pathology, University Hospital Erlangen, Erlangen, Germany.
authors.forename: Arndt
authors.initials: A
authors.lastname: Hartmann
authors.affiliation: Molecular Oncology Group, Institute of Pathology, Medical Faculty of the RWTH Aachen University, Aachen, Germany.
authors.forename: Ruth
authors.initials: R
authors.lastname: Knüchel
authors.affiliation: Molecular Oncology Group, Institute of Pathology, Medical Faculty of the RWTH Aachen University, Aachen, Germany.
authors.forename: Edgar
authors.initials: E
authors.lastname: Dahl
mesh_terms: D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002455:Cell Division; D045744:Cell Line, Tumor; D005260:Female; D020869:Gene Expression Profiling; D016147:Genes, Tumor Suppressor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D008565:Membrane Proteins / Q000502:physiology*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D061251:Primary Cell Culture; D011379:Prognosis; D016016:Proportional Hazards Models; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014162:Transfection; D060449:Wnt Signaling Pathway; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; C117636:SFRP1 protein, human; D000094742:Secreted Frizzled-Related Proteins; C579455:BDNF protein, human