TY - JOUR
T1 - Estrogen and insulin-like growth factor-I (IGF-I) independently down-regulate critical repressors of breast cancer growth
AU - Casa, Angelo J.
AU - Potter, Adam S.
AU - Malik, Simeen
AU - Lazard, Za Waunyka
AU - Kuiatse, Isere
AU - Kim, Hee Tae
AU - Tsimelzon, Anna
AU - Creighton, Chad J.
AU - Hilsenbeck, Susan G.
AU - Brown, Powell H.
AU - Oesterreich, Steffi
AU - Lee, Adrian V.
N1 - Funding Information:
Acknowledgments This work was supported by grants from the Department of Defense Breast Cancer Research Program W81XWH-06-1-0714 (AJC) and BC043880 (SM), and by grants from the National Institutes of Health P01CA30195 (AVL), P30CA58183 (AVL), and R01CA097213 (SO).
PY - 2012/2
Y1 - 2012/2
N2 - Although estrogen receptor alpha (ERα) and insulin-like growth factor (IGF) signaling are important for normal mammary development and breast cancer, cross-talk between these pathways, particularly at the level of transcription, remains poorly understood. We performed microarray analysis on MCF-7 breast cancer cells treated with estradiol (E2) or IGF-I for 3 or 24 h. IGF-I regulated mRNA of five to tenfold more genes than E2, and many genes were co-regulated by both ligands. Importantly, expression of these co-regulated genes correlated with poor prognosis of human breast cancer. Closer examination revealed enrichment of repressed transcripts. Interestingly, a number of potential tumor suppressors, for example, B-cell linker (BLNK), were down-regulated by IGF-I and E2. Analysis of three down-regulated genes showed that E2-mediated repression occurred independently of IGF-IR, and IGF-I-mediated repression occurred independently of ERα. However, repression by IGF-I or E2 required common kinases, such as PI3K and MEK, suggesting downstream convergence of the two pathways. In conclusion, E2 and IGF-I co-regulate a set of genes that affect breast cancer outcome. There is enrichment of repressed transcripts, and, for some genes, the down-regulation is independent at the receptor level. This may be important clinically, as tumors with active ERα and IGF-IR signaling may require co-targeting of both pathways.
AB - Although estrogen receptor alpha (ERα) and insulin-like growth factor (IGF) signaling are important for normal mammary development and breast cancer, cross-talk between these pathways, particularly at the level of transcription, remains poorly understood. We performed microarray analysis on MCF-7 breast cancer cells treated with estradiol (E2) or IGF-I for 3 or 24 h. IGF-I regulated mRNA of five to tenfold more genes than E2, and many genes were co-regulated by both ligands. Importantly, expression of these co-regulated genes correlated with poor prognosis of human breast cancer. Closer examination revealed enrichment of repressed transcripts. Interestingly, a number of potential tumor suppressors, for example, B-cell linker (BLNK), were down-regulated by IGF-I and E2. Analysis of three down-regulated genes showed that E2-mediated repression occurred independently of IGF-IR, and IGF-I-mediated repression occurred independently of ERα. However, repression by IGF-I or E2 required common kinases, such as PI3K and MEK, suggesting downstream convergence of the two pathways. In conclusion, E2 and IGF-I co-regulate a set of genes that affect breast cancer outcome. There is enrichment of repressed transcripts, and, for some genes, the down-regulation is independent at the receptor level. This may be important clinically, as tumors with active ERα and IGF-IR signaling may require co-targeting of both pathways.
KW - Breast cancer
KW - Cross-talk
KW - Estrogen
KW - IGF
KW - Microarray
KW - Transcriptional repression
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U2 - 10.1007/s10549-011-1540-0
DO - 10.1007/s10549-011-1540-0
M3 - Article
C2 - 21541704
AN - SCOPUS:84857915302
SN - 0167-6806
VL - 132
SP - 61
EP - 73
JO - Breast Cancer Research and Treatment
JF - Breast Cancer Research and Treatment
IS - 1
ER -