ABSTRACT
The transcription factor nuclear factor-κB (NF-κB) has important roles for tumorigenesis, but how it regulates cancer stem cells (CSCs) remains largely unclear. We identified insulin-like growth factor 2 (IGF2) is a key target of NF-κB activated by HER2/HER3 signaling to form tumor spheres in breast cancer cells. The IGF2 receptor, IGF1 R, was expressed at high levels in CSC-enriched populations in primary breast cancer cells. Moreover, IGF2-PI3K (IGF2-phosphatidyl inositol 3 kinase) signaling induced expression of a stemness transcription factor, inhibitor of DNA-binding 1 (ID1), and IGF2 itself. ID1 knockdown greatly reduced IGF2 expression, and tumor sphere formation. Finally, treatment with anti-IGF1/2 antibodies blocked tumorigenesis derived from the IGF1Rhigh CSC-enriched population in a patient-derived xenograft model. Thus, NF-κB may trigger IGF2-ID1-IGF2-positive feedback circuits that allow cancer stem-like cells to appear. Then, they may become addicted to the circuits. As the circuits are the Achilles' heels of CSCs, it will be critical to break them for eradication of CSCs.
Subject(s)
Breast Neoplasms/pathology , Gene Expression Regulation, Neoplastic , Inhibitor of Differentiation Protein 1/metabolism , Insulin-Like Growth Factor II/metabolism , Neoplasm Recurrence, Local/pathology , Neoplastic Stem Cells/pathology , Animals , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Carcinogenesis , Female , Humans , Inhibitor of Differentiation Protein 1/genetics , Insulin-Like Growth Factor I/genetics , Insulin-Like Growth Factor I/metabolism , Insulin-Like Growth Factor II/genetics , Mice , Mice, Nude , NF-kappa B/genetics , NF-kappa B/metabolism , Neoplasm Grading , Neoplasm Invasiveness , Neoplasm Metastasis , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/metabolism , Neoplastic Stem Cells/metabolism , Phosphatidylinositol 3-Kinase/genetics , Phosphatidylinositol 3-Kinase/metabolism , Prognosis , Signal Transduction , Spheroids, Cellular , Survival Rate , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
AIMS: Methods of administering (99m)Tc-phytate during sentinel node biopsy of early breast cancer patients were compared to improve the sensitivity of the technique. METHODS: Two injection methods, intradermal vs. intradermal-plus-deep injection, were compared in 648 early breast cancer patients. Intradermal injection was done in 323 consecutive patients (325 breasts), and intradermal-plus-deep injection was done in 325 consecutive patients (329 breasts). The following items were compared: (1) The number of axillary nodes detected scintigraphically and removed surgically, and the breast number of micrometastasis to axillary nodes; (2) The number of internal mammary nodes detected scintigraphically and removed surgically; and (3) The sensitivity of axillary SNB. RESULTS: The number of axillary nodes scintigraphically detected was 1.63+/-0.80 (mean+/-SD) in patients given intradermal injection, and was 1.82+/-0.94 in patients given intradermal-plus-deep injection. The number of axillary nodes surgically removed was 1.78+/-0.93 in patients given intradermal injection, and was 1.95+/-0.99 in patients given intradermal-plus-deep injection. The visualization of internal mammary nodes was superior with intradermal-plus-deep injection (5/325 for intradermal, and 51/329 for intradermal-plus-deep). The putative sensitivity was 71/72 (98.6%) for the intradermal-plus-deep method and 56/62 (90.3%) for the intradermal method. The frequency of detection of micrometastasis was 24 in 71 true positive (38.8%) for the intradermal-plus-deep method and 13 in 56 true positive (23.2%) for the intradermal method. CONCLUSIONS: The SNB procedure with the intradermal-plus-deep injection method detected more axillary and internal mammary nodes, more (not statistically significant) micrometastasis and improved the putative sensitivity more than the SNB procedure with the intradermal injection method.
Subject(s)
Breast Neoplasms/pathology , Organotechnetium Compounds/administration & dosage , Phytic Acid/administration & dosage , Radiopharmaceuticals/administration & dosage , Sentinel Lymph Node Biopsy , Axilla , Breast , Female , Humans , Injections, Intradermal , Lymph Nodes/pathology , Lymphatic Metastasis , Middle Aged , Sensitivity and Specificity , Sentinel Lymph Node Biopsy/methodsABSTRACT
AIMS: The aim of the present study is to clarify the level of radioactive lymph node should be biopsied after the most radioactive SN is removed. METHODS: SNB using radionuclide was performed in our hospital for 1179 primary breast cancers between April 2000 and October 2005; most (1177/1179) were performed successfully. Our criterion for harvesting SNs is to remove tissue until no radioactive site is present. The level of radioactivity and the order of removal of each lymph node were compared with pathologic results. RESULTS: More than 2 (overall average 1.9) radioactive SNs were biopsied in 686 of 1177 breasts. Cancer positive results were recorded for 142 breasts with multiple SNs. In 142 breasts, 64 showed metastasis to the most radioactive node only, 39 showed metastasis other than the most radioactive node only, and 39 showed the most radioactive node and other radioactive nodes. Moreover, if several other criteria were applied, false-positive cases were increased significantly. CONCLUSIONS: It is necessary to harvest radioactive lymph nodes other than the most radioactive. Moreover, efforts to remove every radioactive lymph node will minimize false-negative results.
