title: Influence of secreted frizzled receptor protein 1 (SFRP1) on neoadjuvant chemotherapy in triple negative breast cancer does not rely on WNT signaling.
abstract: BACKGROUND
  Triple negative breast cancer (TNBC) is characterized by lack of expression of both estrogen and progesterone receptor as well as lack of overexpression or amplification of HER2. Despite an increased probability of response to chemotherapy, many patients resistant to current chemotherapy regimens suffer from a worse prognosis compared to other breast cancer subtypes. However, molecular determinants of response to chemotherapy specific to TNBC remain largely unknown. Thus, there is a high demand for biomarkers potentially stratifying triple negative breast cancer patients for neoadjuvant chemotherapies or alternative therapies.
  
  
  METHODS
  In order to identify genes correlating with both the triple negative breast cancer subtype as well as response to neoadjuvant chemotherapy we employed publicly available gene expression profiles of patients, which had received neoadjuvant chemotherapy. Analysis of tissue microarrays as well as breast cancer cell lines revealed correlation to the triple negative breast cancer subtype. Subsequently, effects of siRNA-mediated knockdown on response to standard chemotherapeutic agents as well as radiation therapy were analyzed. Additionally, we evaluated the molecular mechanisms by which SFRP1 alters the carcinogenic properties of breast cancer cells.
  
  
  RESULTS
  SFRP1 was identified as being significantly overexpressed in TNBC compared to other breast cancer subtypes. Additionally, SFRP1 expression is significantly correlated with an increased probability of positive response to neoadjuvant chemotherapy. Knockdown of SFRP1 in triple negative breast cancer cells renders the cells more resistant to standard chemotherapy. Moreover, tumorigenic properties of the cells are modified by knockdown, as shown by both migration or invasion capacity as well reduced apoptotic events. Surprisingly, we found that these effects do not rely on Wnt signaling. Furthermore, we show that pro-apoptotic as well as migratory pathways are differentially regulated after SFRP1 knockdown.
  
  
  CONCLUSIONS
  We could firstly show that SFRP1 strongly correlates with the triple negative breast cancer subtype and secondly, that SFRP1 might be used as a marker stratifying patients to positively respond to neoadjuvant chemotherapy. The mechanisms by which tumor suppressor SFRP1 influences carcinogenic properties of cancer cells do not rely on Wnt signaling, thereby demonstrating the complexity of tumor associated signaling pathways.
authors.affiliation: Translational Tumor Biology Group, Albert-Schweitzer Campus 1 A1, 48149, Münster, Germany. Christof.Bernemann@ukmuenster.de.
authors.forename: Christof
authors.initials: C
authors.lastname: Bernemann
authors.forename: Carolin
authors.initials: C
authors.lastname: Hülsewig
authors.forename: Christian
authors.initials: C
authors.lastname: Ruckert
authors.forename: Sarah
authors.initials: S
authors.lastname: Schäfer
authors.forename: Lena
authors.initials: L
authors.lastname: Blümel
authors.forename: Georg
authors.initials: G
authors.lastname: Hempel
authors.forename: Martin
authors.initials: M
authors.lastname: Götte
authors.forename: Burkhard
authors.initials: B
authors.lastname: Greve
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Barth
authors.forename: Ludwig
authors.initials: L
authors.lastname: Kiesel
authors.forename: Cornelia
authors.initials: C
authors.lastname: Liedtke
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D045744:Cell Line, Tumor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D020360:Neoadjuvant Therapy; D015398:Signal Transduction / Q000187:drug effects; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D000970:Antineoplastic Agents; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C117636:SFRP1 protein, human; D000094742:Secreted Frizzled-Related Proteins