ABSTRACT
ErbB2 (HER2, neu) is a receptor tyrosine kinase overexpressed in about 25% of invasive breast carcinomas. Neutrophil gelatinase-associated lipocalin (NGAL) is a secreted glycoprotein expressed in a variety of cancers, including breast carcinomas. NGAL can inhibit erythroid cell production, leading to anemia. Anemia usually occurs in cancer patients and negatively affects quality of life. However, current treatment for cancer-related anemia has potential complications. ErbB2, NGAL, and anemia have all been associated with increased metastasis and poor prognosis in breast cancer patients, although the relationship between ErbB2 and NGAL expression is not clear. Here, using breast cancer cell lines in vitro and transgenic mice carrying the activated c-neu oncogene driven by a mouse mammary tumor virus (MMTV-neu) in vivo, we show that ErbB2 overexpression leads to NGAL upregulation, which is dependent on nuclear factor-kappaB (NF-kappaB) activity. MMTV-neu transgenic mice developed anemia after tumor onset, and anemia progression could be partially arrested by a NF-kappaB inhibitor and ErbB2-targeted therapy. Taken together, upregulation of NGAL by ErbB2 through NF-kappaB activation is involved in cancer-related anemia, and the ErbB2, NF-kappaB, and NGAL pathways may serve as potential therapeutic targets for cancer-related anemia.
Subject(s)
Acute-Phase Proteins/biosynthesis , Breast Neoplasms/metabolism , Lipocalins/biosynthesis , NF-kappa B/metabolism , Proto-Oncogene Proteins/biosynthesis , Acute-Phase Proteins/genetics , Anemia/blood , Anemia/genetics , Anemia/metabolism , Animals , Antineoplastic Agents/pharmacology , Breast Neoplasms/blood , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Cell Line, Tumor , Female , Humans , Lipocalin-2 , Lipocalins/genetics , Mammary Neoplasms, Experimental/drug therapy , Mammary Neoplasms, Experimental/genetics , Mammary Neoplasms, Experimental/metabolism , Mice , Mice, Transgenic , NF-kappa B/antagonists & inhibitors , Nitriles/pharmacology , Proto-Oncogene Proteins/genetics , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Receptor, ErbB-2/antagonists & inhibitors , Receptor, ErbB-2/biosynthesis , Receptor, ErbB-2/genetics , Signal Transduction , Sulfones/pharmacology , Up-RegulationABSTRACT
Overexpression of the ErbB2 receptor tyrosine kinase is prevalent in approximately 30% of human breast cancers and confers Taxol resistance. Our previous work has shown that ErbB2 inhibits Taxol-induced apoptosis in breast cancer cells by transcriptionally up-regulating p21(Cip1). However, the mechanism of ErbB2-mediated p21(Cip1) up-regulation is unclear. Here, we show that ErbB2 up-regulates p21(Cip1) transcription through increased Src activity in ErbB2-overexpressing cells. Src activation further activated signal transducer and activator of transcription 3 (STAT3) that recognizes a SIE binding site on the p21(Cip1) promoter required for ErbB2-mediated p21(Cip1) transcriptional up-regulation. Both Src and STAT3 inhibitors restored Taxol sensitivity in resistant ErbB2-overexpressing breast cancer cells. Our data suggest that ErbB2 overexpression can activate STAT3 through Src leading to transcriptional up-regulation of p21(Cip1) that confers Taxol resistance of breast cancer cells. Our study suggests a potential clinical application of Src and STAT3 inhibitors in Taxol sensitization of ErbB2-overexpressing breast cancers.
