ABSTRACT
Aurora B is a serine/threonine kinase that has been implicated in regulating cell proliferation in distinct cancers, including breast cancer. Here we show that Aurora B expression is elevated in basal-like breast cancer (BLBC) compared with other breast cancer subtypes. This high level of expression seems to correlate with poor metastasis-free survival and relapse-free survival in affected patients. Mechanistically, we show that elevated Aurora B expression in breast cancer cells activates AKT/GSK3ß to stabilize Snail1 protein, a master regulator of epithelial-mesenchymal transition (EMT), leading to EMT induction in a kinase-dependent manner. Conversely, Aurora B knock down by short-hairpin RNAs (shRNAs) suppresses AKT/GSK3ß/Snail1 signaling, reverses EMT and reduces breast cancer metastatic potential in vitro and in vivo. Finally, we identified a specific OCT4 phosphorylation site (T343) responsible for mediating Aurora B-induced AKT/GSK3ß/Snail1 signaling and EMT that could be attenuated by Aurora B kinase inhibitor treatment. These findings support that Aurora B induces EMT to promote breast cancer metastasis via OCT4/AKT/GSK3ß/Snail1 signaling. Pharmacologic Aurora B inhibition might be a potential effective treatment for breast cancer patients with metastatic disease.
Subject(s)
Aurora Kinase B/metabolism , Breast Neoplasms/metabolism , Carcinoma, Ductal/metabolism , Epithelial-Mesenchymal Transition , Neoplasm Metastasis , Snail Family Transcription Factors/metabolism , Animals , Aurora Kinase B/antagonists & inhibitors , Breast Neoplasms/pathology , Carcinoma, Ductal/pathology , Cell Line, Tumor , Down-Regulation , Female , Glycogen Synthase Kinase 3 beta/metabolism , Humans , Lung Neoplasms/secondary , Mice , Mice, Inbred NOD , Neoplasm Invasiveness , Octamer Transcription Factor-3/metabolism , Organophosphates/pharmacology , Phosphorylation , Protein Kinase Inhibitors/pharmacology , Protein Stability , Quinazolines/pharmacology , Signal Transduction , Triple Negative Breast Neoplasms/metabolismABSTRACT
Breast cancers enduring treatment with chemotherapy may be enriched for cancer stem cells or tumor-initiating cells, which have an enhanced capacity for self-renewal, tumor initiation, and/or metastasis. Breast cancer cells that express the type I tyrosine kinaselike orphan receptor ROR1 also may have such features. Here we find that the expression of ROR1 increased in breast cancer cells following treatment with chemotherapy, which also enhanced expression of genes induced by the activation of Rho-GTPases, Hippo-YAP/TAZ, or B lymphoma Mo-MLV insertion region 1 homolog (BMI1). Expression of ROR1 also enhanced the capacity of breast cancer cells to invade Matrigel, form spheroids, engraft in Rag2-/-[Formula: see text] mice, or survive treatment with paclitaxel. Treatment of mice bearing breast cancer patient-derived xenografts (PDXs) with the humanized anti-ROR1 monoclonal antibody cirmtuzumab repressed expression of genes associated with breast cancer stemness, reduced activation of Rho-GTPases, Hippo-YAP/TAZ, or BMI1, and impaired the capacity of breast cancer PDXs to metastasize or reengraft Rag2-/-[Formula: see text] mice. Finally, treatment of PDX-bearing mice with cirmtuzumab and paclitaxel was more effective than treatment with either alone in eradicating breast cancer PDXs. These results indicate that targeting ROR1 may improve the response to chemotherapy of patients with breast cancer.
Subject(s)
Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Drug Resistance, Neoplasm/drug effects , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/metabolism , Receptor Tyrosine Kinase-like Orphan Receptors/metabolism , Adenosine Triphosphatases/metabolism , Animals , Antibodies, Monoclonal , Breast/drug effects , Breast/metabolism , Cell Line, Tumor , Female , Gene Expression Regulation, Neoplastic/drug effects , Heterografts , Humans , Mice , NIH 3T3 Cells , Nuclear Proteins/metabolism , Paclitaxel/pharmacology , Polycomb Repressive Complex 1/metabolism , Protein Serine-Threonine Kinases/metabolism , Transcription Factors/metabolismABSTRACT
Caffeine, an antagonist of the adenosine receptor A1R, is used as a dietary supplement to reduce body weight, although the underlying mechanism is unclear. Here, we report that adenosine level in the cerebrospinal fluid, and hypothalamic expression of A1R, are increased in the diet-induced obesity (DIO) mouse. We find that mice with overexpression of A1R in the neurons of paraventricular nucleus (PVN) of the hypothalamus are hyperphagic, have glucose intolerance and high body weight. Central or peripheral administration of caffeine reduces the body weight of DIO mice by the suppression of appetite and increasing of energy expenditure. We also show that caffeine excites oxytocin expressing neurons, and blockade of the action of oxytocin significantly attenuates the effect of caffeine on energy balance. These data suggest that caffeine inhibits A1Rs expressed on PVN oxytocin neurons to negatively regulate energy balance in DIO mice.
