Date on Master's Thesis/Doctoral Dissertation

12-2009

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Pharmacology and Toxicology

Committee Chair

Lillard, James W. Jr.

Author's Keywords

Breast cancer; Chemokines; CXCR4; CXCR7

Subject

Breast--Cancer--Research

Abstract

Interactions between chemokines and their receptors are involved in organ- specific homing and propagation of metastatic breast cancer (BrCa) cells. BrCa cells express higher levels of CXCR4 and CXCR7 mRNA and cell surface protein, than normal human mammary epithelial cells (HMECs). CXCR4 is ubiquitously expressed by a multitude of cancerous and normal cell types; while CXCR7 is differentially expressed by T helper lymphocytes, cancer cells, and normal epithelium. Importantly, recent studies show CXCR7 is highly expressed by activated endothelial cells (i.e., neovasculature), fetal liver cells, and many tumors, but not by non-transformed (or normal) human tissues. Unlike other chemokine receptors, activation of CXCR7 does not cause Ca 2+ mobilization/flux or cell migration. However, CXCR7 activation by its ligands (CXCL12 or CXCL11) provides signals for growth, survival, and adhesion. Preliminary studies demonstrated CXCR7 expression is significantly higher in BrCa cases than compared to non-neoplastic tissues. Further, CXCR7 mRNAs are elevated in the BrCa cell line MCF-7, with modest expression in MDA-MB-231 when compared to HMEC. Other studies revealed cell-type specific expression of CXCR7 may modulate BrCa progression. Together, these findings provided the rationale to support the hypothesis that CXCR7 and its interactions with CXCR4 and CXCL12 promote BrCa cell collagenase expression, alter NF-?B and ERK1/2 localization to the nucleus, and correlates with cell cycle. Two Specific Aims were used to test this hypothesis. Aim 1 - Determined the differential and cell cycle-dependent expression of CXCR7, CXCR4, CXCL12, matrix metalloproteinase proteins MMP-1 and/or -13 in BrCa cells, which were affected by CXCL12 stimulation. Aim 2 - Characterize some of the CXCL12-dependent mechanisms involved in BrCa progression. The results from this study indicate that differential and cell cycle-dependent CXCR7 and CXCR4 expression plays a critical role in enhancing BrCa cell invasion and survival cell signals, which were CXCL12-dependent but often G protein independent. Further, CXCL12-induced CXCR4 mRNA expression required G ß? protein and/or JAK/STAT signal transduction. It was also shown that CXCL12-mediated CXCR7 mRNA expression in a pertussis toxin sensitive and no doubt required Gai protein signaling. In confirmation with previous studies from Wendt et al., CXCL12 expression is negatively regulated by the presence of CXCR4. Lastly, CXCL12-dependent MMP-1 and MMP-13 mRNA expression is Ga protein-, Gß protein-, and G? protein-dependent presumably through CXCR4, while elevated expression of CXCR7 suppresses these effects.

Download

Share

COinS