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

Breast Cancer Res Treat. 2012 Feb;132(1):61-73. doi: 10.1007/s10549-011-1540-0. Epub 2011 May 4.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Benzimidazoles / pharmacology
  • Biomarkers, Tumor / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Proliferation*
  • Disease-Free Survival
  • Down-Regulation
  • Estradiol / analogs & derivatives
  • Estradiol / pharmacology
  • Estradiol / physiology*
  • Estrogen Receptor alpha / antagonists & inhibitors
  • Estrogen Receptor alpha / metabolism
  • Female
  • Fulvestrant
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Genes, Tumor Suppressor
  • Humans
  • Insulin-Like Growth Factor I / pharmacology
  • Insulin-Like Growth Factor I / physiology*
  • Kaplan-Meier Estimate
  • Oligonucleotide Array Sequence Analysis
  • Prognosis
  • Pyridones / pharmacology
  • Receptor, IGF Type 1 / antagonists & inhibitors
  • Receptor, IGF Type 1 / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • B cell linker protein
  • BMS 536924
  • Benzimidazoles
  • Biomarkers, Tumor
  • Estrogen Receptor alpha
  • Pyridones
  • estrogen receptor alpha, human
  • Fulvestrant
  • Estradiol
  • Insulin-Like Growth Factor I
  • Receptor, IGF Type 1