Silencing growth hormone receptor inhibits estrogen receptor negative breast cancer through ATP-binding cassette sub-family G member 2

Abstract

Growth hormone receptor (GHR) plays a vital role in breast cancer chemoresistance and metastasis but the mechanism is not fully understood. We determined if GHR could be a potential therapeutic target for estrogen receptor negative (ER−ve) breast cancer, which are highly chemoresistant and metastatic. GHR was stably knocked down in ER-ve breast cancer cells and its effect on cell proliferation, metastatic behavior, and chemosensitivity to docetaxel (DT) was assessed. Microarray analysis was performed to identify potential GHR downstream targets involved in chemoresistance. GHR and ATP-binding cassette sub-family G member 2 (ABCG2) overexpression and knockdown studies were performed to investigate the mechanism of GHR-induced chemoresistance. Patient-derived xenografts was used to study the effect of GHR and ABCG2. Immunohistochemical data was used to determine the correlation between GHR, pAKT, pmTOR, and ABCG2 expressions. GHR silencing drastically reduced the chemoresistant and metastatic behavior of ER-ve breast cancer cells and also inhibited AKT/mTOR pathway. In contrast, activation, or overexpression of GHR increased chemoresistance and metastasis by increasing the expression and promoter activity, of ABCG2. Inhibition of JAK2/STAT5 signaling repressed GHR-induced ABCG2 promoter activity and expression. Further, ABCG2 knockdown significantly increased the chemosensitivity. Finally, patient-derived xenograft studies revealed the role of GHR in chemoresistance. Overall, these findings demonstrate that targeting GHR could be a novel therapeutic approach to overcome chemoresistance and associated metastasis in aggressive ER-ve breast cancers.Breast cancer: A protein to target for double effectA new way to treat some forms of breast cancer might be achieved by drugs that interact with a cell surface protein that binds to growth hormone and transmits growth-inducing signals into the cells. Rajkumar Lakshmanaswamy and colleagues at Texas Tech University, El Paso, USA, investigated the role of growth hormone receptor (GHR) protein in human breast cancer cells. Silencing the gene for GHR dramatically reduced the ability of the cells to multiply and spread, and also reduced the cells’ resistance to anti-cancer drugs. Increasing the activity of the GHR gene increased the cells’ cancerous activity and their resistance to chemotherapy. The research identified some molecular signaling pathways inside cells that mediated these effects. Drugs interfering with GHR activity might inhibit the spread of cancer while making existing cancer cells more susceptible to treatment.