GRK3 as a regulator of CXCL12/CXCR4 breast cancer metastasis (2014)

Undergraduate: Kelsey Miller

Faculty Advisor: Teresa Tarrant
Department: Applied Sciences

---

Triple Negative Breast Cancer are invasive, metastatic tumors that lack the three cellular receptors that are most commonly targeted by current chemotherapies: Estrogen Receptor (ER), Progesterone Receptor (PR), and Human Epidermal Growth Factor Receptor- 2 (Her2). With limited treatment options, this diagnosis typically carries poor prognosis. The CXCL12/CXCR4 signaling pathway is known to play a role in breast cancer metastasis. G protein coupled receptor kinase 3 (GRK3) is a negative regulator of CXCR4 activity. We show that GRK3 knockdown breast cancer cells exhibit a more metastatic phenotype in vivo than wild type cell lines. Additionally, we have found cells that expressed lower levels of GRK3 may express higher transcript levels of matrix metallopeptidase-9 (MMP9) or Vascular endothelial growth factor (VEGF), two genes known to be associated with metastasis. AMD3100, a current chemotherapy drug in the clinical trial stages, is a CXCR4 antagonist. We have tested the effect of this drug on both in vitro gene transcription and in vivo metastatic potential. The metastatic potential of GRK3 knockdown breast cancer cells was evaluated using the non-invasive method of bioluminescent imaging. In vivo data suggests that AMD3100 treatment has no effect on metastatic potential in our mouse model and may, in fact, exacerbate tumor growth and metastasis. Our results show a role for GRK3 in the regulation of CXCR4 signals that relate to breast cancer metastasis.