Author of

• 11481

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  P2.02 - Poster Session 2 - Novel Cancer Genes and Pathways (ID 148)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Biology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/29/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 11502

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    P2.02-021 - Implications of CXCR4 and Estrogen/Progesterone Receptor (ER/PR) pathway activity in Non Small Cell Lung Cancer (NSCLC) (ID 3431)

    15:10 - 15:27  |  Author(s): A. Klimowicz
    • Abstract

    Background
    CXCR4 is a chemokine receptor that activates signaling pathways responsible for trafficking of cells to sites of inflammation, retention of stem cells in the bone marrow and plays a role in migration and metastatic processes in tumour cells. Previous work by the Bebb lab demonstrated that female stage IV NSCLC patients with high CXCR4 expression have significantly worse survival compared to their low CXCR4 expressing counterparts. Recently, a positive regulatory loop was discovered linking CXCR4 and ER signaling pathways leading to increased gene expression of SDF-1 and other ER dependent genes. We explored the relationship between CXCR4 and ER/PR signaling in NSCLC cell lines, and assessed the expression of ER/PR in stage IV tissue samples to determine if ER/PR could be contributing to the observed gender dependent difference in clinical outcome seen in CXCR4 high expressers.

    Methods
    Two male and two female NSCLC cell lines were characterized for ER and CXCR4 by western blot. Activity of the CXCR4 and ER pathways in each cell line after stimulation with SDF-1 and estradiol (E2), respectively, were assessed by western blot of downstream signaling targets ERK, AKT, phospho-ER and PR. Cross activity of the CXCR4 and ER pathways was examined by stimulating cells with E2 and quantifying SDF-1 and PR mRNA by rtPCR. Tumor specimens from stage IV NSCLC patients (Glans-Look Lung Cancer Database) previously assessed for CXCR4 were analyzed for ERα and PR expression by quantitative immunohistochemistry (IHC) using the HistoRx AQUA® platform. Correlation between CXCR4 and ER/PR expression was assessed using Pearson’s rank correlation, and associations between marker expression and clinical factors/overall survival were assessed using a Cox proportional hazards model.

    Results
    All cell lines expressed varying levels of CXCR4, ERα and ERβ, and were responsive to both SDF-1 and E2 stimulation. Preliminary data suggests that activation of AKT and ERK after stimulation with SDF-1 occurs more rapidly in the male cell lines than in the female cell lines, and that there were differences in SDF-1 gene expression after E2 stimulation between the male and female lines. Other experiments are ongoing and full data will be presented. ER and PR AQUA scores were obtained for 131 patients (63 females and 68 males). There were weak positive correlations between both ER/CXCR4 (r = 0.153) and PR/CXCR4 (r = 0.278), however, only the correlation between CXCR4 and PR was significant (p = 0.002). Similarly, only PR expression was significantly associated with overall survival in the model (p = 0.03)(HR = 1.46). More detailed sub-group analyses further exploring the association with gender is ongoing, and will be presented.

    Conclusion
    The CXCR4 and ER pathways are active in NSCLC cell lines. There appears to be differences in the responsiveness of male and female NSCLC cell lines to CXCR4 and ER pathway activation. ERs and PRs are present in stage IV NSCLC tissue samples, and are associated with both CXCR4 expression and overall survival in our patient cohort. The full implication of these observations is still being investigated and further analyses will be presented.