Estrogen and insulin-like growth factor-I (IGF-I) independently down-regulate critical repressors of breast cancer growth

Abstract

Although estrogen receptor (ER) 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 gene transcription, remains poorly understood. We performed microarray analysis on MCF-7 breast cancer cells treated with estradiol (E2) or IGF-I for 3hr or 24hr. IGF-I regulated mRNA of 5-10-fold 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 patients. Closer examination revealed enrichment of repressed transcripts (compared to induced transcripts).. Interestingly, a number of potential tumor suppressors were down-regulated by IGF-I and estradiol, suchas the B-cell linker BLNK Analysis of three down-regulated genes showed that E2-mediated repression occurred independently of IGF-IR, and IGF-I-mediated repression occurred independently of ER. However, repression by IGF-I or estradiol required common downstream kinases, such as PI3K and MEK, suggesting downstream conversion 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 the down-regulation by E2 and IGF-I is independent at the receptor level. This may be important clinically, as tumors with active ER and IGF-IR signaling may require co-targeting of both pathways.

Targeting Insulin and Insulin-Like Growth Factor Signaling in Breast Cancer

“…Beyond mTOR inhibitors, other small molecule inhibitors of the downstream pathways, such as PI3K inhibitor LY294002 [66], S6K1 inhibitor H89 [57], MAPK inhibitor U0126 [57, 67], and dual PI3K/mTOR inhibitor NVP-BEZ235 [68] are currently in preclinical and clinical studies. The important translation initiation protein 4EBP1 could also be a potential drug target to terminate IGF/insulin signaling induced cap-dependent translation.…”

Caffeine and Caffeic Acid Inhibit Growth and Modify Estrogen Receptor and Insulin-like Growth Factor I Receptor Levels in Human Breast Cancer

“…The ER and IGFIR signaling systems are tightly linked and subject to feedback cross-talk. For example, estrogen and IGFs coregulate several genes that affect breast cancer outcome (5). In addition, hyperactive IGFIR-PI3K-Akt signaling has been implicated to contribute in the acquisition of resistance to endocrine therapy during breast cancer progression (6).…”

Insulin-like Growth Factor-I Receptor (IGF-IR) Translocates to Nucleus and Autoregulates IGF-IR Gene Expression in Breast Cancer Cells

“…The interplay between the IGF and estrogen signaling pathways has been the focus of significant basic and translational interest (23)(24)(25)(26). The IGFs and estrogen act in a synergistic fashion in breast epithelial cells (27), and both the MAPK and Akt pathways were shown to mediate the activation of ER␣ by IGF-I (28,29).…”