Center of Emphasis in Cancer Research, Texas Tech University Health Sciences Center El Paso, El Paso, TX, 79905, USA.
Research Core Laboratory, Texas Tech University Health Sciences Center El Paso, El Paso, TX, 79905, USA.
Exp Mol Med. 2019 Jan 7;51(1):1-13. doi: 10.1038/s12276-018-0197-8.
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.
生长激素受体（GHR）在乳腺癌化疗耐药和转移中发挥着重要作用，但机制尚不完全清楚。我们确定 GHR 是否可以成为雌激素受体阴性（ER-ve）乳腺癌的潜在治疗靶点，因为这种癌症具有高度的化疗耐药性和转移性。我们在 ER-ve 乳腺癌细胞中稳定敲低 GHR，并评估其对细胞增殖、转移行为和对多西紫杉醇（DT）的化疗敏感性的影响。进行了微阵列分析，以鉴定参与化疗耐药的潜在 GHR 下游靶标。进行了 GHR 和 ABC 盒亚家族 G 成员 2（ABCG2）过表达和敲低研究，以研究 GHR 诱导的化疗耐药的机制。使用患者来源的异种移植来研究 GHR 和 ABCG2 的作用。免疫组织化学数据用于确定 GHR、pAKT、pmTOR 和 ABCG2 表达之间的相关性。GHR 沉默显着降低了 ER-ve 乳腺癌细胞的化疗耐药性和转移性行为，并抑制了 AKT/mTOR 通路。相比之下，GHR 的激活或过表达通过增加 ABCG2 的表达和启动子活性来增加化疗耐药性和转移。抑制 JAK2/STAT5 信号转导抑制了 GHR 诱导的 ABCG2 启动子活性和表达。此外，ABCG2 敲低显着增加了化疗敏感性。最后，患者来源的异种移植研究揭示了 GHR 在化疗耐药中的作用。总的来说，这些发现表明靶向 GHR 可能是克服侵袭性 ER-ve 乳腺癌化疗耐药和相关转移的新治疗方法。
