Low doses of paclitaxel enhance liver metastasis of breast cancer cells in the mouse model.
Paclitaxel is the most commonly used chemotherapeutic agent in breast cancer treatment. In addition to its well-known cytotoxic effects, recent studies have shown that paclitaxel has tumor-supportive activities. Importantly, paclitaxel levels are not maintained at the effective concentration through one treatment cycle; rather, the concentration decreases during the cycle as a result of drug metabolism. Therefore, a comprehensive understanding of paclitaxel's effects requires insight into the dose-specific activities of paclitaxel and their influence on cancer cells and the host microenvironment. Here we report that a low dose of paclitaxel enhances metastasis of breast cancer cells to the liver in mouse models. We used microarray analysis to investigate gene expression patterns in invasive breast cancer cells treated with low or clinically relevant high doses of paclitaxel. We also investigated the effects of low doses of paclitaxel on cell migration, invasion and metastasis in vitro and in vivo. The results showed that low doses of paclitaxel promoted inflammation and initiated the epithelial-mesenchymal transition, which enhanced tumor cell migration and invasion in vitro. These effects could be reversed by inhibiting NF-κB. Furthermore, low doses of paclitaxel promoted liver metastasis in mouse xenografts, which correlated with changes in estrogen metabolism in the host liver. Collectively, these findings reveal the paradoxical and dose-dependent effects of paclitaxel on breast cancer cell activity, and suggest that increased consideration be given to potential adverse effects associated with low concentrations of paclitaxel during treatment.



Gene expression microarray data are available in the GEO database under accession number GSE82048.
Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China.
Qi
Q
Li
Department of Immunology, Center for Human Disease Genomics, School of Basic Medical Science, Peking University Health Science Centre, Beijing, China.
Zhuang
Z
Ma
Surgery Department, Peking University First Hospital, Beijing, China.
Yinhua
Y
Liu
Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China.
Xiaoxi
X
Kan
Department of Immunology, Center for Human Disease Genomics, School of Basic Medical Science, Peking University Health Science Centre, Beijing, China.
Changjun
C
Wang
Department of Immunology, Center for Human Disease Genomics, School of Basic Medical Science, Peking University Health Science Centre, Beijing, China.
Bingnan
B
Su
Department of Immunology, Center for Human Disease Genomics, School of Basic Medical Science, Peking University Health Science Centre, Beijing, China.
Yuchen
Y
Li
Department of Immunology, Center for Human Disease Genomics, School of Basic Medical Science, Peking University Health Science Centre, Beijing, China.
Yingmei
Y
Zhang
Department of Immunology, Center for Human Disease Genomics, School of Basic Medical Science, Peking University Health Science Centre, Beijing, China.
Pingzhang
P
Wang
Department of Immunology, Center for Human Disease Genomics, School of Basic Medical Science, Peking University Health Science Centre, Beijing, China.
Yang
Y
Luo
Department of Immunology, Center for Human Disease Genomics, School of Basic Medical Science, Peking University Health Science Centre, Beijing, China.
Daxiang
D
Na
Department of Immunology, Center for Human Disease Genomics, School of Basic Medical Science, Peking University Health Science Centre, Beijing, China.
Lanlan
L
Wang
Department of Immunology, Center for Human Disease Genomics, School of Basic Medical Science, Peking University Health Science Centre, Beijing, China.
Guoying
G
Zhang
Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China.
Xiaoxin
X
Zhu
Department of Immunology, Center for Human Disease Genomics, School of Basic Medical Science, Peking University Health Science Centre, Beijing, China.
Lu
L
Wang
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000633:toxicity*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D004967:Estrogens / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000556:secondary*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness; D017239:Paclitaxel / Q000008:administration & dosage / Q000633:toxicity*
D000972:Antineoplastic Agents, Phytogenic; D004967:Estrogens; D018836:Inflammation Mediators; D016328:NF-kappa B; D017239:Paclitaxel
breast cancer metastasis; cancer related inflammation; epithelial-mesenchymal transition; estrogen metabolism; paclitaxel