TCDD causes suppression of growth and differentiation of MCF10A, human mammary epithelial cells by interfering with their insulin receptor signaling through c-Src kinase and ERK activation

Sujin Park, Olga Mazina, Akira Kitagawa, Patrick Wong, Fumio Matsumura

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

One of the proposed mechanisms of carcinogenic action of TCDD (=dioxin) on breast cells is that it causes significant inhibition of proper differentiation of mammary duct epithelial cells and thereby increases the number of terminal end buds, which are susceptible to other carcinogens (Fenton et al., Toxicol Sci 2002;67:63-74; Brown et al., Carcinogenesis 1998; 19:1623-1629; Lamartiniere, J Mammary Gland Biol Neoplasia 2002;7:67-76). To address this topic, we selected MCF10A, a line of immortalized normal human breast epithelial cells as an in vitro model. An initial effort was made to optimize the cultural condition of MCF10A cells to promote the cell differentiation effect of insulin. Under this condition, TCDD clearly antagonized the action of insulin only in the presence of cholera toxin that is known to promote the differentiation of normal human breast epithelial cells. To test the hypothesis that TCDD-induced c-Src kinase activation is casually related to this compound's antagonistic action against insulin, we treated MCF10A cells with two c-Src blocking agents, an anti-Src antisense oligonucleotides blocker and a known specific inhibitor of c-Src kinase, PP-2 and studied the effect of insulin and TCDD on cell proliferation. The results showed that, in cells treated with either of these two c-Src blocking agents, the antagonistic effect of TCDD disappeared. It was also found that agents which specifically block the activation of ERK could also abrogate the action of TCDD to suppress insulin signaling. Together, these results indicate that the mechanism of the antagonistic action of TCDD on insulin signaling is mainly mediated through c-Src signaling through activation of ERK.

Original languageEnglish (US)
Pages (from-to)322-331
Number of pages10
JournalJournal of Biochemical and Molecular Toxicology
Volume18
Issue number6
DOIs
StatePublished - Jan 1 2005
Externally publishedYes

Keywords

  • Dioxin
  • Insulin Signaling
  • MCF10A Breast Epithelial Cells
  • Src tyrosine kinase
  • TCDD

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Toxicology
  • Health, Toxicology and Mutagenesis

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