PKIB Inhibits Autophagy to Regulate Tamoxifen Resistance in Breast Cancer with Estrogen Receptor-Positive Status

Background: Tamoxifen is an adjuvant endocrine drug used as first-line therapy for treating breast cancer (BC) with positive estrogen receptor (ER) status. However, its effectiveness is limited by the emergence of tamoxifen resistance (TR) caused by changes in autophagy. The aim of this research was to evaluate the role of the cyclic adenosine monophosphate (cAMP)-dependent protein kinase inhibitor-beta (PKIB) in the emergence of TR in BC, together with its involvement in autophagy. Methods: PKIB expression was assessed in tamoxifen-sensitive and -resistant BC cell lines and clinical specimens using RTqPCR, Western blotting, and immunohistochemistry. Overexpression and knockdown of PKIB were employed to evaluate the effects on autophagy and on the response to tamoxifen in vitro. In addition, the mechanism of PKIB-mediated TR was explored using immunofluorescence and Western blot analysis. Furthermore, the activation of cAMP-responsive element-binding protein (CREB)/Autophagy related gene 7 (ATG7) signaling after knockdown of PKIB was evaluated in MCF7 and T47D cells. Results: PKIB was found to be upregulated in tamoxifen-sensitive cell lines (MCF7 and T47D) and in primary tumor tissues. Knockdown of PKIB promoted TR, both in vivo and in vitro, and markedly increased autophagy levels in tamoxifen-sensitive cells. In contrast, the overexpression of PKIB suppressed autophagy and restored tamoxifen sensitivity in TR cells. Furthermore, the protein levels of ATG7 and pCREB were upregulated in MCF7/si2-PKIB and T47D/si2-PKIB cells. Lastly, Kaplan-Meier survival analysis showed that upregulation of PKIB was associated with favourable prognosis of BC patients. Conclusions: This study demonstrated that PKIB inhibits autophagy via the CREB/ATG7 axis, thereby leading to TR in BC.