Abstract
The RET tyrosine kinase signaling pathway is involved in the development of endocrine resistant ER+ breast cancer. However, we know little about how ER+ cells activate RET signaling and initiate an endocrine resistant phenotype. Here we show that both ER+ endocrine resistant and sensitive breast cancers have a functional RET tyrosine kinase signaling pathway, but that endocrine sensitive breast cancer cells lack RET ligands that are necessary to drive endocrine resistance. Transcription of one RET ligand, GDNF, is necessary and sufficient to confer resistance in the ER+ MCF-7 cell line. Endogenous GDNF produced by endocrine resistant cells is translated, secreted into the media, and activates RET signaling in nearby cells. In patients, RET ligand expression predicts responsiveness to endocrine therapies and correlates with survival. Collectively, our findings show that ER+ tumor cells are “poised” for RET mediated endocrine resistance, expressing all components of the RET signaling pathway, but endocrine sensitive cells lack high expression of RET ligands that are necessary to initiate the resistance phenotype.
Highlights
Estrogen receptor alpha (ERα) is the major driver of ~75% of all breast cancers
We used Precision Run-On and Sequencing (PRO-seq) to map the location and orientation of RNA polymerase in two tamoxifen sensitive (TamS) and two de novo resistant (TamR) MCF-7 cell lines that were clonally derived from parental MCF-7 cells [9]
We have used genomic tools to dissect how the glial cell line-derived neurotrophic factor (GDNF)-RET signaling pathway becomes activated in breast cancer cells to promote resistance to endocrine therapies
Summary
Estrogen receptor alpha (ERα) is the major driver of ~75% of all breast cancers. Current therapies for patients ith ER+ breast cancer are largely aimed at blocking the ERα signaling pathway. Tamoxifen blocks ERα function by competitively inhibiting E2/ERα interactions [1] and fulvestrant promotes ubiquitin-mediated degradation of ERα [2]. Endocrine therapies are estimated to have reduced breast cancer mortality by 25–30% [3]. Despite the widespread success of endocrine therapies, approximately 40–50% of breast cancer patients will either present with endocrine-resistant breast cancer at the time of diagnosis or progress into endocrine-resistant disease during the course of treatment [4]. There remains an urgent need to further elucidate the mechanism of endocrine resistance
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