A deletion mutant of heregulin increases the sensitivity of breast cancer cells to chemotherapy without promoting tumorigenicity

Ella Atlas, Kozystof Bojanowski, Inderjit Mehmi, Ruth Lupu

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Heregulin (HRG) is an activator of the erbB2-, erbB3-and erbB4-(erbB-2/3/4) signaling pathway. Transfection of full-length HRG cDNA into the estrogen (E2)-dependent cell line MCF-7 promoted an invasive E2-independent phenotype, as well as persistent activation of the erbB-2/3/4 receptors. Moreover, HRG expression in MCF-7 cells renders the cells sensitive to the topoisomerase II inhibitor doxorubicin (Doxo). In an attempt to dissociate the tumorigenic effect of HRG from the sensitizing effect to chemotherapy, we constructed a structural deletion mutant of HRG. Transfection of the deletion mutant of HRG described in this study (HRG/M) into MCF-7 cells resulted in the dissociation of the tumor-promoting activity of HRG from the sensitization to Doxo, that is, although the cells did not become more aggressive or E2-independent they became more sensitive to Doxo. HRG/M was unable to autophosphorylate the erbB receptors and did not affect the level of MAPK phosphorylation. Furthermore, the intracellular localization of the protein was different from that of the full-length protein. Our data show that the HRG/M sequences are sufficient to sensitize MCF-7 cells to Doxo, and provide evidence that this sensitization is independent of erbB2 activation.

Original languageEnglish (US)
Pages (from-to)3441-3451
Number of pages11
JournalOncogene
Volume22
Issue number22
DOIs
StatePublished - May 29 2003

Keywords

  • Antiestrogen resistance
  • Breast cancer
  • Doxorubicin
  • Drug resistance
  • Estrogen dependence
  • HRG
  • Mutants

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Fingerprint Dive into the research topics of 'A deletion mutant of heregulin increases the sensitivity of breast cancer cells to chemotherapy without promoting tumorigenicity'. Together they form a unique fingerprint.

Cite this