Abstract
The mechanisms of metastatic progression from hormonal therapy (HT) are largely unknown in luminal breast cancer. Here we demonstrate the enrichment of CD133(hi)/ER(lo) cancer cells in clinical specimens following neoadjuvant endocrine therapy and in HT refractory metastatic disease. We develop experimental models of metastatic luminal breast cancer and demonstrate that HT can promote the generation of HT-resistant, self-renewing CD133(hi)/ER(lo)/IL6(hi) cancer stem cells (CSCs). HT initially abrogates oxidative phosphorylation (OXPHOS) generating self-renewal-deficient cancer cells, CD133(hi)/ER(lo)/OXPHOS(lo). These cells exit metabolic dormancy via an IL6-driven feed-forward ER(lo)-IL6(hi)-Notch(hi) loop, activating OXPHOS, in the absence of ER activity. The inhibition of IL6R/IL6-Notch pathways switches the self-renewal of CD133(hi) CSCs, from an IL6/Notch-dependent one to an ER-dependent one, through the re-expression of ER. Thus, HT induces an OXPHOS metabolic editing of luminal breast cancers, paradoxically establishing HT-driven self-renewal of dormant CD133(hi)/ER(lo) cells mediating metastatic progression, which is sensitive to dual targeted therapy.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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AC133 Antigen
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Anastrozole
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Androstadienes
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Animals
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Antigens, CD / metabolism
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Antineoplastic Agents, Hormonal*
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Bone Neoplasms / genetics*
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Bone Neoplasms / secondary
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Breast Neoplasms / genetics*
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Breast Neoplasms / pathology
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Carcinoma, Ductal, Breast / genetics*
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Carcinoma, Ductal, Breast / secondary
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Carcinoma, Lobular / genetics*
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Carcinoma, Lobular / secondary
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Cell Line, Tumor
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Cell Self Renewal / genetics*
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Drug Resistance, Neoplasm / genetics*
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Estradiol / analogs & derivatives
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Female
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Flow Cytometry
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Fulvestrant
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Gene Expression Regulation, Neoplastic*
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Glycoproteins / metabolism
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Humans
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In Vitro Techniques
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Interleukin-6 / genetics
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Letrozole
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Leuprolide
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MCF-7 Cells
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Mice, Inbred NOD
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Mice, SCID
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Neoplasm Metastasis
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Neoplasm Transplantation
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Neoplastic Stem Cells / metabolism*
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Nitriles
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Oxidative Phosphorylation
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Peptides / metabolism
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Real-Time Polymerase Chain Reaction
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Receptor, Notch3
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Receptors, Estrogen / metabolism
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Receptors, Notch / genetics
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Signal Transduction / genetics
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Tamoxifen
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Triazoles
Substances
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AC133 Antigen
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Androstadienes
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Antigens, CD
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Antineoplastic Agents, Hormonal
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Glycoproteins
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Interleukin-6
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NOTCH3 protein, human
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Nitriles
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PROM1 protein, human
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Peptides
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Prom1 protein, mouse
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Receptor, Notch3
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Receptors, Estrogen
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Receptors, Notch
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Triazoles
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Tamoxifen
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Fulvestrant
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Anastrozole
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Estradiol
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Letrozole
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Leuprolide
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exemestane