Insulin-like growth factor-I receptor signaling in tamoxifen-resistant breast cancer: a supporting role to the epidermal growth factor receptor

Endocrinology. 2005 Nov;146(11):4609-18. doi: 10.1210/en.2005-0247. Epub 2005 Jul 21.


There is considerable evidence that the epidermal growth factor receptor (EGFR) and IGF-I receptor (IGF-IR) cross-talk in breast cancer cells. In the present study, we have examined whether EGFR/IGF-IR cross-talk exists in EGFR-positive tamoxifen-resistant variants of MCF-7 (Tam-R) and T47D (T47D-R) breast cancer cell lines. Although Tam-R cells expressed reduced IGF-IR protein levels compared with their wild-type MCF-7 counterparts, phosphorylated IGF-IR protein levels were equivalent in the two cell lines under basal growth conditions, possibly as a consequence of increased IGF-II expression in Tam-R cells. IGF-II activated both IGF-IR and EGFR in Tam-R cells, whereas only activation of IGF-IR was observed in wild-type cells. In contrast, epidermal growth factor rapidly induced EGFR, but not IGF-IR, phosphorylation in Tam-R cells. IGF-II promoted direct association of c-SRC with IGF-IR, phosphorylated c-SRC, and increased EGFR phosphorylation at tyrosine 845, a c-SRC-dependent phosphorylation site. Pretreatment with either AG1024 (IGF-IR-specific inhibitor) or an IGF-II neutralizing antibody inhibited basal IGF-IR, c-SRC, and EGFR phosphorylation, and AG1024 significantly reduced Tam-R basal cell growth. The c-SRC inhibitor SU6656 also inhibited growth, reduced basal and IGF-II-induced c-SRC and EGFR phosphorylation, and blocked EGFR activation by TGFalpha. Similarly, in T47D-R cells, AG1024 and SU6656 inhibited basal and IGF-II-induced phosphorylation of c-SRC and EGFR, and SU6656 reduced TGFalpha-induced EGFR activity. These results suggest the existence of a unidirectional IGF-IR/EGFR cross-talk mechanism whereby IGF-II, acting through the IGF-IR, regulates basal and ligand-activated EGFR signaling and cell proliferation in a c-SRC-dependent manner in Tam-R cells. This cross-talk between IGF-IR and EGFR is not unique to Tam-R cells because this mechanism is also active in a tamoxifen-resistant T47D-R cell line.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Hormonal / pharmacology*
  • Breast Neoplasms / physiopathology*
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm*
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / drug effects
  • ErbB Receptors / metabolism*
  • Female
  • Humans
  • Insulin-Like Growth Factor II / pharmacology
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins pp60(c-src) / metabolism
  • Receptor Cross-Talk
  • Receptor, IGF Type 1 / antagonists & inhibitors
  • Receptor, IGF Type 1 / metabolism*
  • Signal Transduction*
  • Tamoxifen / pharmacology*
  • Transforming Growth Factor alpha / pharmacology


  • Antineoplastic Agents, Hormonal
  • Transforming Growth Factor alpha
  • Tamoxifen
  • Insulin-Like Growth Factor II
  • ErbB Receptors
  • Receptor, IGF Type 1
  • Proto-Oncogene Proteins pp60(c-src)