Emerging evidence has implicated
G protein-coupled receptors, such as CXCR4 and PAR2, in
breast cancer progression and the development of metastatic
breast cancer. However, the role of
proteins that regulate the function of these receptors, such as
arrestins, in
breast cancer has yet to be determined. Examination of the expression of the two nonvisual
arrestins, arrestin2 and 3, in various
breast cancer cell lines revealed comparable expression of
arrestin3 in basal and
luminal lines while arrestin2 expression was much higher in the
luminal lines compared to the more aggressive basal lines. Analysis of normal human breast tissue revealed that arrestin2 and 3 were expressed in both
luminal and myoepithelial cells of mammary epithelia with arrestin2 highest in myoepithelial cells and
arrestin3 comparable in both cell types. Quantitative immunofluorescence-based examination of primary
breast tumors revealed that arrestin2 expression significantly decreased with
cancer progression from
ductal carcinoma in situ to invasive
carcinoma and further to
lymph node metastasis (P < 0.001). Moreover, decreased arrestin2 expression was associated with decreased survival (P = 0.0007) as well as positive lymph node status and increased
tumor size and nuclear grade. In contrast,
arrestin3 expression significantly increased during
breast cancer progression (P < 0.001) and increased expression was associated with decreased survival (P = 0.014).
Arrestin3 was also an independent prognostic marker of
breast cancer with a hazard ratio of 1.65. Overall, these studies demonstrate that arrestin2 levels decrease while
arrestin3 levels increase during
breast cancer progression and these changes correlate with a poor clinical outcome.