Si-Wu-Tang and its constituents promote mammary duct cell proliferation by up-regulation of HER-2 signaling.
OBJECTIVE
The consumption of over-the-counter natural products by perimenopausal women remains a challenging problem. It is our aim to investigate the proliferative effect of Si-Wu-Tang (SWT) and its constituents on MCF7 breast cancer cells as well as the SWT-modulated cell signaling and HER-2 gene expression.


METHODS
By using the MCF7 (ER+, HER-2 low), BT474 (ER+, HER-2 high), MDAMB231 (ER-, HER-2 low), and SKBR3 (ER-, HER-2 high) mammary duct cell lines as our in vitro model, the mitogenic effects of SWT and its constituents were assessed by trypan blue dye exclusion assay and DNA flow cytometry. SWT-modulated cell signaling and HER-2 gene expression were evaluated in the MCF7 line by Western blot and reverse transcriptase-polymerase chain reaction analyses.


RESULTS
The results showed that SWT and some of its constituents dose-dependently stimulated cell proliferation of MCF7 cells. The activation of HER-2, its downstream signaling molecules AKT and ERK1/2, as well as HER-2 gene up-regulation were involved in SWT-stimulated cell proliferation. The addition of neutralizing antibody against HER-2 abrogated the SWT-up-regulated HER-2 expression, indicating a positive feedback control for the action of HER-2 in this setting. Ferulic acid, one of the major compounds in SWT, not only promoted cell proliferation of MCF7, BT474, MDAMB231, and SKBR3 cells, but also increased the phosphorylation of HER-2, AKT, and ERK1/2, as well as overexpression of HER-2, on MCF7 cells.


CONCLUSIONS
We conclude that SWT and its active constituents stimulate mammary duct cell proliferation by modulating HER-2, PI3K/AKT, and MAPK signaling and the positive feedback of HER-2 gene expression. This provides important information for perimenopausal women who are at risk of or have breast cancer or other growths in breast tissue.
Chang
Chun-Ju
CJ
Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC.
Chiu
Jen-Hwey
JH
Tseng
Ling-Ming
LM
Chang
Chuan-Hsiung
CH
Chien
Tsu-Ming
TM
Chen
Chien-Chih
CC
Wu
Chew-Wun
CW
Lui
Wing-Yiu
WY
D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D018734:Genes, erbB-2 / Q000187:drug effects*; D006801:Humans; D042361:Mammary Glands, Human / Q000166:cytology / Q000187:drug effects*; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D010936:Plant Extracts / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation
D004365:Drugs, Chinese Herbal; D047628:Estrogen Receptor alpha; D010936:Plant Extracts; C403258:si-wu-tang; D020928:Mitogen-Activated Protein Kinases