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.

The effects of growth hormone on therapy resistance in cancer

“…Analysis of murine tumor xenografts in immunocompetent C57BL6/J mouse models of GH excess, e.g., the bovine (b) GH transgenic mouse (bGH), found significantly upregulated ABC-transporters compared to wildtype littermates and verified our in vitro observations (unpublished results). Another very recent study in estrogen receptor negative breast cancer cells and in patient-derived nude mice xenografts treated with docetaxel, shRNA mediated silencing of GHR indeed suppressed multi-drug efflux pump ABCG2 and re-sensitized the tumors to the anti-cancer agent [149] , thereby providing additional evidence to GHRmediated induction of drug efflux via upregulated ABC-transporter expression. GHR silencing appeared to concomitantly increase drug-induced apoptosis, and reduced cell viability, migration and invasion properties of the breast cancer cells in vitro and in vivo [149] .…”

Deficiency in Dipeptidyl Peptidase-4 Promotes Chemoresistance Through the CXCL12/CXCR4/mTOR/TGFβ Signaling Pathway in Breast Cancer Cells

“…Patients with diabetes and cancer have a poor prognosis after treatment with chemotherapy or surgery with a high mortality compared with those without diabetes [2,3]. Chemotherapy is the primary treatment choice for metastatic patients, and chemoresistance is associated with metastasis in breast cancer [37]. Chemoresistance is associated with the EMT.…”

Growth hormone receptor promotes breast cancer progression via the BRAF/MEK/ERK signaling pathway

“…GHR, a member of the class I cytokine receptor family, has been reported to be associated with breast cancer development and progression . Here, we attempted to find one mechanism underlying the influence of GHR on breast cancer progression.…”

“…GHR silencing also inhibits GH‐induced chemoresistance in breast cancer cells with positive estrogen receptor . In addition, overexpression of GHR is found to enhance chemoresistance and metastasis of estrogen receptor–negative breast cancer . These reports suggest that GHR may be a potential therapeutic target for breast cancer and GH‐induced chemoresistance.…”