Heregulin β1 promotes breast cancer cell proliferation through Rac/ERK-dependent induction of cyclin D1 and p21Cip1

Chengfeng Yang, Eric Klein, Richard K. Assoian, Marcelo G. Kazanietz

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Accumulating evidence indicates that heregulins, EGF (epidermal growth factor)-like ligands, promote breast cancer cell proliferation and are involved in the progression of breast cancer towards an aggressive and invasive phenotype. However, there is limited information regarding the molecular mechanisms that mediate these effects. We have recently established that HRG (heregulin β1) promotes breast cancer cell proliferation and migration via cross-talk with EGFR (EGF receptor) that involves the activation of the small GTPase Rac1. In the present paper we report that Rac1 is an essential player for mediating the induction of cyclin D1 and p21Cip1 by HRG in breast cancer cells. Inhibition of Rac function by expressing either the Rac-GAP (GTPase-activating protein) β2-chimaerin or the dominant-negative Rac mutant N17Rac1, or Rac1 depletion using RNAi (RNA interference), abolished the cyclin D1 and p21Cip1 induction by HRG. Interestingly, the proliferative effect of HRG was impaired not only when the expression of Rac1 or cyclin D1 was inhibited, but also when cells were depleted of p21 Cip1 using RNAi. Inhibition of EGFR, PI3K (phosphoinositide 3-kinase; kinases required for Rac activation by HRG) or MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase] also blocked the up-regulation of cyclin D1 and p21Cip1 by HRG. In addition, we found that HRG activates NF-κB (nuclear factor κB) in a Rac1-and MEK-dependent fashion, and inhibition of NF-κB abrogates cyclin D1/p21Cip1 induction and proliferation by HRG. Taken together, these findings establish a central role for Rac1 in the control of HRG-induced breast cancer cell-cycle progression and proliferation through up-regulating the expression of cyclin D1 and p21Cip1.

Original languageEnglish (US)
Pages (from-to)167-175
Number of pages9
JournalBiochemical Journal
Volume410
Issue number1
DOIs
StatePublished - Feb 15 2008
Externally publishedYes

Fingerprint

Neuregulin-1
Cyclin D1
Cell proliferation
Cell Proliferation
Breast Neoplasms
Phosphotransferases
Mitogen-Activated Protein Kinase Kinases
RNA Interference
Epidermal Growth Factor Receptor
Chemical activation
Cells
RNA
GTPase-Activating Proteins
1-Phosphatidylinositol 4-Kinase
Monomeric GTP-Binding Proteins
Extracellular Signal-Regulated MAP Kinases
Phosphatidylinositols
Mitogen-Activated Protein Kinases
Phosphatidylinositol 3-Kinases
Epidermal Growth Factor

All Science Journal Classification (ASJC) codes

  • Medicine(all)
  • Biochemistry

Cite this

Yang, Chengfeng ; Klein, Eric ; Assoian, Richard K. ; Kazanietz, Marcelo G. / Heregulin β1 promotes breast cancer cell proliferation through Rac/ERK-dependent induction of cyclin D1 and p21Cip1. In: Biochemical Journal. 2008 ; Vol. 410, No. 1. pp. 167-175.
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Heregulin β1 promotes breast cancer cell proliferation through Rac/ERK-dependent induction of cyclin D1 and p21Cip1. / Yang, Chengfeng; Klein, Eric; Assoian, Richard K.; Kazanietz, Marcelo G.

In: Biochemical Journal, Vol. 410, No. 1, 15.02.2008, p. 167-175.

Research output: Contribution to journalArticle

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