leuprolide and Carcinoma--Ductal--Breast

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.

Topics: AC133 Antigen; Anastrozole; Androstadienes; Animals; Antigens, CD; Antineoplastic Agents, Hormonal; Bone Neoplasms; Breast Neoplasms; Carcinoma, Ductal, Breast; Carcinoma, Lobular; Cell Line, Tumor; Cell Self Renewal; Drug Resistance, Neoplasm; Estradiol; Female; Flow Cytometry; Fulvestrant; Gene Expression Regulation, Neoplastic; Glycoproteins; Humans; In Vitro Techniques; Interleukin-6; Letrozole; Leuprolide; MCF-7 Cells; Mice, Inbred NOD; Mice, SCID; Neoplasm Metastasis; Neoplasm Transplantation; Neoplastic Stem Cells; Nitriles; Oxidative Phosphorylation; Peptides; Real-Time Polymerase Chain Reaction; Receptor, Notch3; Receptors, Estrogen; Receptors, Notch; Signal Transduction; Tamoxifen; Triazoles

Topics: Anastrozole; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Breast Neoplasms; Carcinoma, Ductal, Breast; Carcinoma, Intraductal, Noninfiltrating; Carmustine; Chemoradiotherapy; Craniotomy; Cyclophosphamide; Decanoic Acids; Disease-Free Survival; Doxorubicin; Female; Humans; Leuprolide; Nitriles; Paclitaxel; Polyesters; Radiosurgery; Receptors, Estrogen; Triazoles; Young Adult

Topics: Adult; Antineoplastic Agents, Hormonal; Breast Neoplasms; Carcinoma, Ductal, Breast; Chemotherapy, Adjuvant; Cryopreservation; Embryo, Mammalian; Female; Fertility; Gene Expression Profiling; Humans; Leuprolide; Lymph Node Excision; Mammography; Mastectomy, Segmental; Neoplasm Staging; Prognosis; Radiotherapy, Adjuvant; Receptor, ErbB-2; Receptors, Estrogen; Risk Assessment; Secondary Prevention; Sentinel Lymph Node Biopsy; Tamoxifen; Ultrasonography, Mammary

Topics: Anastrozole; Androstadienes; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Aromatase Inhibitors; Bone Neoplasms; Breast Neoplasms, Male; Carcinoma, Ductal, Breast; Chemotherapy, Adjuvant; Humans; Letrozole; Leuprolide; Lung Neoplasms; Lymphatic Metastasis; Male; Mastectomy, Modified Radical; Middle Aged; Nitriles; Receptors, Estrogen; Receptors, Progesterone; Treatment Outcome; Triazoles