Metastatic capacities are fundamental features of
tumor malignancy.
ADP-ribosylation factor (ARF) 1 has emerged as a key regulator of invasion in
breast cancer cells. However, the importance of this
GTPase, in vivo, remains to be demonstrated. We report that ARF1 is highly expressed in
breast tumors of the most aggressive and advanced subtypes. Furthermore, we show that lowered expression of ARF1 impairs growth of primary
tumors and inhibits lung
metastasis in a murine xenograft model. To understand how ARF1 contributes to invasiveness, we used a poorly invasive
breast cancer cell line, MCF7 (ER+), and examined the effects of overexpressing ARF1 to levels similar to that found in invasive cell lines. We demonstrate that ARF1 overexpression leads to the epithelial-mesenchymal transition (EMT). Mechanistically, ARF1 controls cell-cell adhesion through ß-
catenin and
E-cadherin, oncogenic Ras activation and expression of EMT inducers. We further show that ARF1 overexpression enhances invasion, proliferation and resistance to a chemotherapeutic agent. In vivo, ARF1 overexpressing MCF7 cells are able to form more
metastases to the lung. Overall, our findings demonstrate that ARF1 is a molecular switch for
cancer progression and thus suggest that limiting the expression/activation of this
GTPase could help improve outcome for
breast cancer patients.