Chemokine receptor CXCR4-mediated transformation of mammary epithelial cells by enhancing multiple RTKs expression and deregulation of the p53/MDM2 axis.

Recent studies have shown that CXCR4 is associated with tumor metastasis. Elevated levels of CXCR4 are also detected in a high percentage of DCIS cases. The high frequency of CXCR4 expression in DCIS suggests that many DCIS cases are "primed" for invasiveness. In this study, we demonstrated that expression of CXCR4 reveals morphological alterations in cells, from normal acinar morphological epithelial cells to a more invasive morphology in a 3D-culture system. Ectopic expression of CXCR4 induces invasion of MCF-10A cells. Interestingly, CXCR4 is capable of orchestrating a complex alteration in signaling networks, which include upregulation of multiple receptor tyrosine kinases (RTKs), deregulation of p53/MDM2 axis, upregulation of E-cadherin and c-myc, as well as modulation of cell cycle molecules to facilitate mammary epithelia cell transformation. These findings reveal that CXCR4 expression exerts a critical role in early stages of breast lesions, which may explain the high frequency of CXCR4 expression detected in DCIS. We believe that these studies will lead to new, biologically-based therapeutic strategies for clinical intervention, prevention and treatments of breast cancer.

CXCR4 suppression attenuates EGFRvIII-mediated invasion and induces p38 MAPK-dependent protein trafficking and degradation of EGFRvIII in breast cancer cells.

Our previous report has shown that the constitutively activated EGFR variant, EGFRvIII, up-regulates the pro-metastatic chemokine receptor CXCR4 in breast cancer cells. Here we evaluated the biological effect and cell signaling effects of silencing CXCR4 expression in EGFRvIII-expressing breast cancer cells. Short hairpin RNA (shRNA)-mediated suppression of CXCR4 expression significantly reduced the invasive potential and proliferation of EGFRvIII-expressing breast cancer cells. These cells exhibited a reduction of EGFRvIII activity and protein expression due to increased protein degradation and altered protein trafficking. In conclusion, suppression of CXCR4 inhibits EGFRvIII-mediated breast cancer cell invasion and proliferation.