The role of the chemokine receptor CXCR4 in EGFRvIII-expressing breast
      cancer

Rahimi, Massod.

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Rahimi, Massod.

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Thesis (Ph.D.)--Georgetown University, 2009.; Includes bibliographical references.; Text (Electronic thesis) in PDF format. The ligand-independent, constitutively active Epidermal Growth Factor Receptor (EGFR) variant, EGFRvIII, is a potent tumor-specific oncogene found in many human cancers, including breast cancer. EGFRvIII has various oncogenic functions, including enhancing breast cancer cell invasion, and its expression is correlated with disease progression and metastasis in human breast cancer.; Chemokines and their receptors are essential for normal development and physiology and are also involved in numerous human diseases, most importantly cancer progression and metastasis. CXCR4 has been extensively studied since its identification as a molecule involved in the "homing" of cancer cells to sites which express the CXCR4 cognate ligand, SDF-1 (CXCL12). ErbB2 enhances the expression of CXCR4, and was shown to be required for ErbB2-mediated invasion in vitro and lung metastasis in vivo, and co-expression of CXCR4 with both wild-type EGFR and ErbB2 has been shown to be correlated with an increased breast cancer metastases and poor prognosis. However, the impact of CXCR4 expression in the invasive phenotype of EGFRvIII-expressing breast cancer is unknown.; This study reveals that EGFRvIII increased expression of CXCR4 transcriptionally, and post-translationally by decreasing molecules involved in the internalization, recycling, cellular trafficking, and degradation of CXCR4 in breast cancer cells regardless of estrogen receptor status or endogenous levels of other ErbB-receptors. EGFRvIII-expressing breast cancer cells also had significantly higher CXCL12/CXCR4 mediated invasion in comparison to parental cells that have high levels of ErbB2, signifying an even more important role for CXCR4 in EGFRvIII-induced invasiveness. Suppression of CXCR4 expression in EGFRvIII-expressing breast cancer cells with short hair-pin RNA (shRNA) significantly inhibited breast cancer cell invasion and also decreased cell proliferation. Further investigation revealed that knocking-down CXCR4 expression decreased EGFRvIII expression by increasing EGFRvIII protein trafficking and subsequent degradation through increased activity of p38 MAPK. Finally, since the use of anti-EGFR targeted therapies in the clinic may be limited and EGFR mutants are often associated with resistance to conventional anticancer therapies, the well-tolerated natural, antitumor compound, 3,3'-Diindolylmethane (DIM) was shown to inhibit the invasion and proliferation of breast cancer, glioma, and lung cancer cells expressing EGFR mutants.