Abstract 5839: Growth hormone receptor (GHR) expression confers resistance to ruxolitinib in endocrine-resistant breast cancer cells
Authors: Holtz Anja N. , Yee Douglas , Beckwith Heather 
Published: August 2018

Abstract
More than 30% of patients with early-stage estrogen receptor-positive breast cancer (ER+) treated with adjuvant endocrine therapy will relapse within fifteen years and all patients with metastatic breast cancer expressing ER eventually acquire resistance to antiestrogen therapy. The insulin-like growth factor 1 (IGF-1) and its receptor (IGF-1R) are involved in the development of resistance to endocrine therapies such as tamoxifen. The IGF-1/growth hormone (GH) signaling axis has been implicated as a mitogenic pathway in the development and progression of breast carcinogenesis. Preclinical data demonstrate that blockade of the IGF-1R inhibits breast cancer growth, progression, and drug resistance. Unfortunately, IGF-1R targeted therapies have failed to show a benefit in prolonging either disease-free or overall survival in clinical trials. IGF-1R inhibition results in upregulation of GH due to disruption of a negative feedback pathway. We propose GH is able to stimulate mitogenic pathways independently of IGF-IR and the GHR is a potential therapeutic target in endocrine-resistant breast cancers. Tamoxifen-resistant (TamR) and long-term estrogen deprived (LTED) cells were derived from parental MCF-7L and T47D estrogen receptor-positive breast cancer cells. The endocrine-resistant cell lines express increased levels of growth hormone receptor (GHR) mRNA compared to the parental cell lines from which they were derived when measured by RT-PCR. TamR and LTED cell lines have reduced IGF-1R expression, but continue to phosphorylate insulin receptor substrate 1(IRS-1) downstream of IGF-1R. In these endocrine-resistant cells, GH treatment activates protein kinase B (Akt), phosphoinositide 3-kinase (PI3K), and mitogen activated protein kinase (MAPK) pathways in the absence of IGF-1. To determine if GHR signals through janus kinase-2 (JAK-2) in these cells, we treated MCF-7L and T47D TamR cells with 500 nM GH, which resulted in JAK-2 phosphorylation. To examine growth effects, we treated cells with the JAK-2 inhibitor ruxolitinib. Both MCF-7L and T47D endocrine-resistant cell lines treated with ruxolitinib have increased IC50 values compared to their parental counterparts. The MCF-7L parental cells had an IC50 value of 6.7 µM compared to 20 µM and 21.7 µM in TamR and LTED cells, respectively. The T47D parental cells had an IC50 value of 28.6 µM whereas the IC50 of T47D TamR cells was 45 µM. These data indicate endocrine-resistant breast cancer cell lines with elevated GHR expression have decreased sensitivity to JAK-2 inhibition. Based on these results, GHR and its downstream signaling should be considered as a target in the development of novel therapeutics to treat breast cancers that are resistant to traditional endocrine therapies.
Citation Format: Anja N. Holtz, Douglas Yee, Heather Beckwith. Growth hormone receptor (GHR) expression confers resistance to ruxolitinib in endocrine-resistant breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5839.