The adipokine resistin is linked to insulin resistance and has been shown to be upregulated in breast cancer patients. Previously we demonstrated that high levels of newly identified resistin receptor Adenylate Cyclase-Associated Protein-1 (CAP1) in breast tumors was associated with impaired prognosis. We here aim to delineate the molecular linkage between resistin, CAP1 and breast cancer prognosis.
In estrogen receptor (ER)-positive T47D and ER-negative MDA-MB-231 breast cancer cells, CAP1 expression was silenced by 80-90% using small interfering RNA. Functional effects of reduced CAP1 expression and resistin exposure on cell proliferation, colony formation, and signaling pathways were subsequently investigated.
Initial experiments showed that CAP1 knock down resulted in reduced proliferation of both ER-positive T47D and ER-negative MDA-MB-231 cells by approximately 35 and 40%, respectively, P < 0.0001. CAP1 knock down further decreased the colony formation of T47D and MDA-MB-231 cells by 15 and 20%, respectively, compared with control. Resistin-stimulated T47D cells displayed increased CAP1 and STAT3 protein expression. Resistin exposure induced STAT3 activation in MDA-MB-231 cells, which was reduced following CAP1 knock down.
These results indicate that CAP1 is mechanistically important for both ER-positive and ER-negative breast cancer cell proliferation, supporting our earlier clinical results. This could be mediated by the putative resistin-CAP1-STAT3 signaling pathway. Further clinical and experimental studies are ongoing to elucidate the role of resistin-CAP1 in breast cancer prognosis. These studies could provide a biological insight into how factors contributing to obesity and insulin resistance could impact breast cancer.
Lund University.
Swedish Cancer Society, the Swedish Research Council, the Governmental Funding of Clinical Research within the National Health Service (ALF), the Lund University Hospital Fund, the Swedish Breast Cancer Group (BRO), the Albert Pahlsson Foundation, the Mrs. Berta Kamprad Foundation, the Gyllenstienska Krapperup Foundation and the Royal Physiographic Society in Lund.
All authors have declared no conflicts of interest.