Chemotherapy-induced tumor gene expression changes in human breast cancers.
OBJECTIVE
Studying chemotherapy-induced gene expression changes in vivo, which could provide insights into mechanisms of chemotherapy resistance.


METHODS
We analyzed and compared tumor gene expression changes of about 38 500 genes before and 3 weeks after doxorubicin or docetaxel treatment in 47 breast cancer patients.


RESULTS
By using the median expression level of each probe set as the parameter, less than 5% of genes were upregulated or downregulated by more than 50% after treatment with either drug. Doxorubicin and docetaxel concordantly induced 251 genes predominantly involved in protein and macromolecule metabolism (upregulated), and cell cycle and DNA/RNA metabolism (downregulated). Doxorubicin treatment resulted in coregulation of a cluster of 345 probe sets involved in focal adhesion, Jak-Stat signaling pathway, cell adhesion molecules, and natural killer cell mediated cytotoxicity, whereas docetaxel treatment resulted in coregulation of a cluster of 448 probe sets involved in focal adhesion, neurodegenerative disorders, sphingolipid metabolism, and cell cycle. Tumors that were intrinsically sensitive or resistant to doxorubicin or docetaxel evoked distinct gene expression changes in response to the drug; doxorubicin-resistant tumors upregulated genes that were enriched for ErbB signaling, ubiquitin-mediated proteolysis, TGF-beta signaling, and MAP-kinase signaling pathways, whereas docetaxel-resistant tumors upregulated genes that were enriched for focal adhesion and regulation of actin cytoskeleton. The drug-specific tumor gene expression changes were validated in independent in-vitro and in-vivo datasets.


CONCLUSIONS
Gene expression alterations of breast cancer were specific to doxorubicin and docetaxel treatment, and yielded mechanistic insights into resistance to either drug. Gene expression analysis provides more global perspectives on resistance pathways that could be exploited for therapeutic selection.
Departments of aHaematology-Oncology bSurgery, National University Hospital cNational Cancer Centre, Singapore dUniversity of North Carolina, Chapel Hill, USA.
Soo-Chin
SC
Lee
Xin
X
Xu
Yi-Wan
YW
Lim
Philip
P
Iau
Norita
N
Sukri
Siew-Eng
SE
Lim
Hui Ling
HL
Yap
Wee-Lee
WL
Yeo
Patrick
P
Tan
Sing-Huang
SH
Tan
Howard
H
McLeod
Boon-Cher
BC
Goh
D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D000077143:Docetaxel; D004317:Doxorubicin / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D043823:Taxoids / Q000627:therapeutic use*
D000903:Antibiotics, Antineoplastic; D043823:Taxoids; D000077143:Docetaxel; D004317:Doxorubicin