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OR34-1 Regulation of Breast Cancer Stem Cells by Nuclear Receptor Co-Regulatory Proteins
Despite highly effective treatments for breast cancer (BC), recurrence remains a significant risk among node-positive patients. Breast cancer stem or stem-like progenitor cells (BCSCs herein) are non-proliferative, evade first-line therapies in resistant breast tumors, and account for high mortality...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Endocrine Society
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6554840/ http://dx.doi.org/10.1210/js.2019-OR34-1 |
Sumario: | Despite highly effective treatments for breast cancer (BC), recurrence remains a significant risk among node-positive patients. Breast cancer stem or stem-like progenitor cells (BCSCs herein) are non-proliferative, evade first-line therapies in resistant breast tumors, and account for high mortality among patients with advanced disease. Our objective is to define the signaling pathways that drive cell fate transitions associated with endocrine resistance and the survival and expansion of BCSCs, with the goal of blocking these pathways to impact breast cancer survival. Filling this knowledge gap will pave the way for interventions that increase endocrine therapy duration and specifically target BCSC populations within heterogeneous luminal tumors. We recently defined the steroid receptor (SR) co-regulator, PELP1, as a mediator of BCSC expansion. Utilizing mass spectrometry, we identified steroid receptor coactivator-3, SRC-3, as a novel and preferential interactor with cytoplasmic PELP1. Notably, cytoplasmic PELP1 elevated SRC-3 activation, as measured by SRC-3 phosphorylation at Thr24 and Ser857. SRC-3 knockdown blocked cytoplasmic PELP1-induced BCSC expansion measured using tumorsphere assays, suggesting an essential role for PELP1/SRC-3 complexes in BCSC outgrowth. To better understand PELP1-regulated pathways we performed RNA-seq on MCF7 models grown in tumorsphere conditions to enrich for BCSC populations. We found that cells expressing cytoplasmic PELP1 have a dramatically different global gene profile relative to cells expressing wt-PELP1 (i.e. nuclear). Stem cell biology, metabolic, and hypoxic gene signatures were differentially upregulated, including members of the bi-functional kinase/phosphatase family (PFKFBs). Seahorse metabolic phenotype tests demonstrate that cytoplasmic PELP1 expression influences cellular metabolism by increasing both glycolysis and mitochondrial respiration. Recent studies have implicated pSer857 SRC-3 as a key substrate of PFKFB4 in lung and breast cancer metastases. Furthermore, we found that cytoplasmic PELP1 interacts with PFKFB3 and PFKFB4, and inhibition of PFKFB3 kinase activity blocks PELP1-induced tumorsphere formation. Together, our data suggests that PELP1, SRC-3, and PFKFBs form cytoplasmic signaling complexes that reprogram cellular metabolism to promote BCSC expansion. Our work will lead to the development of targeted therapies against BCSCs that can be used in combination with current treatments to overcome endocrine therapy resistance. |
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