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.
Highlights
Breast cancer is a heterogeneous disease with diverse subtypes
We demonstrate that Growth hormone receptor (GHR) is positively associated with ER−ve breast tumor progression, chemoresistance, and metastasis and find that GHR could serve as a potential therapeutic target for the treatment of aggressive breast cancers
The overexpression of GHR observed in primary breast cancer tissues and aggressive mouse mammary tumors suggest the involvement of GHR in breast cancer
Summary
Breast cancer is a heterogeneous disease with diverse subtypes. Among the breast cancer subtypes, patients with estrogen receptor-positive (ER+ve) breast cancers have a better prognosis[1,2,3]. Edu) 1Center of Emphasis in Cancer Research, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA 2Research Core Laboratory, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA Full list of author information is available at the end of the article. The currently available therapies for metastatic breast cancer prolong patient survival for an average of only 9 months owing to the development of chemoresistance[12]. Overcoming chemoresistance is a major hurdle in the treatment of ER−ve breast cancers, which poses a serious of recurrent metastatic breast cancer associated with
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