Heregulin regulates the actin cytoskeleton and promotes invasive properties in breast cancer cell lines.

Hijazi, Mai; Thompson, Erik W.; Tang, Catherine; Coopman, Peter J.; Torri, Jeffrey A.; Yang, Dajun; Mueller, Susette C.; Lupu, Ruth

doi:10.3892/ijo.17.4.629

Cited by 54 publications

(64 citation statements)

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“…Most studies have focused on NRG effects. NRG is mitogenic for most mammary carcinoma cell lines, 82,[222][223][224][225] and can also stimulate motility and invasiveness of these cells. 209,[225][226][227] In ERBB2-over-expressing breast tumor cells, G1 progression after NRG stimulation was associated with ERBB2 transactivation of ERBB3 and stimulation of the PI3K pathway.…”

Section: Erbb3 In Normal and Neoplastic Tissues Cell Transformation Bmentioning

confidence: 99%

“…NRG is mitogenic for most mammary carcinoma cell lines, 82,[222][223][224][225] and can also stimulate motility and invasiveness of these cells. 209,[225][226][227] In ERBB2-over-expressing breast tumor cells, G1 progression after NRG stimulation was associated with ERBB2 transactivation of ERBB3 and stimulation of the PI3K pathway. 228 Contributions of ERBB3 and/or the ERBB2/ ERBB3 complex to these phenotypic effects of NRG has been confirmed by use of anti-ERBB2 or anti-ERBB3 antibodies 211,212,229 or of a dominant-negative ERBB3 construct.…”

Section: Erbb3 In Normal and Neoplastic Tissues Cell Transformation Bmentioning

confidence: 99%

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The ERBB3 receptor in cancer and cancer gene therapy

2008

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ERBB3, a member of the epidermal growth factor receptor (EGFR) family, is unique in that its tyrosine kinase domain is functionally defective. It is activated by neuregulins, by other ERBB and nonERBB receptors as well as by other kinases, and by novel mechanisms. Downstream it interacts prominently with the phosphoinositol 3-kinase/AKT survival/mitogenic pathway, but also with GRB, SHC, SRC, ABL, rasGAP, SYK and the transcription regulator EBP1. There are likely important but poorly understood roles for nuclear localization and for secreted isoforms. Studies of ERBB3 expression in primary cancers and of its mechanistic contributions in cultured cells have implicated it, with varying degrees of certainty, with causation or sustenance of cancers of the breast, ovary, prostate, certain brain cells, retina, melanocytes, colon, pancreas, stomach, oral cavity and lung. Recent results link high ERBB3 activity with escape from therapy targeting other ERBBs in lung and breast cancers. Thus a wide and centrally important role for ERBB3 in cancer is becoming increasingly apparent. Several approaches for targeting ERBB3 in cancers have been tested or proposed. Small inhibitory RNA (siRNA) to ERBB3 or AKT is showing promise as a therapeutic approach to treatment of lung adenocarcinoma.

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Section: Erbb3 In Normal and Neoplastic Tissues Cell Transformation Bmentioning

confidence: 99%

Section: Erbb3 In Normal and Neoplastic Tissues Cell Transformation Bmentioning

confidence: 99%

The ERBB3 receptor in cancer and cancer gene therapy

2008

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“…Nevertheless the role of HRG in vivo remains to be explained. This factor has been associated in vitro with induction of cell proliferation (Holmes et al, 1992;Aguilar et al, 1999), invasion (Hijazi et al, 2000), apoptosis (Daly et al, 1997), differentiation (Peles et al, 1992;Bacus et al, 1993) and inhibition of cell proliferation (Hamburger and Yoo, 1997;Xu et al, 1997).…”

Section: Molecular and Cellular Pathologymentioning

confidence: 99%

Activation of AKT/PKB in breast cancer predicts a worse outcome among endocrine treated patients

2002

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Akt/PKB is a serine/threonine protein kinase that regulates cell cycle progression, apoptosis and growth factor mediated cell survival in association with tyrosine kinase receptors. The protein is a downstream effector of erbB-2 with implications in breast cancer progression and drug resistance in vitro. We aimed to examine the role of Akt-1 in breast cancer patients, by determining whether the expression (Akt-1) and/or activation (pAkt) were related to prognostic markers and survival. The expression of erbB-2, heregulin b1 and Bcl-2 was also assessed by flow cytometry or immunohistochemistry. This study comprised 93 patients, aged 550 who were treated with tamoxifen and/or goserelin. We found that pAkt was associated with lower S-phase fraction (P=0.001) and the presence of heregulin b1-expressing stromal cells (P=0.017). Neither Akt-1 nor pAkt was related with other factors. Tumour cells-derived heregulin b1 was found mainly in oestrogen receptor negative (P=0.026) and node negative (P=0.005) cases. Survival analysis revealed that pAkt positive patients were more prone to relapse with distant metastasis, independently of S-phase fraction and nodal status (multivariate analysis; P=0.004). The results suggest that activation of Akt may have prognostic relevance in breast cancer.

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“…This cell line expresses low levels of erbB-2 and erbB-3, . We have further shown that antibodies generated against HRG markedly reduce in vitro growth, motility, and invasion of breast cancer cells that overexpress HRG, indicating that HRG is essential for breast cancer cell proliferation, motility, and invasion in vitro (Hijazi et al, 2000). In the light of these observations, we hypothesize that HRG is a tumor-promoting factor that acts independently of erbB-2 overexpression.…”

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confidence: 91%

Blockage of heregulin expression inhibits tumorigenicity and metastasis of breast cancer

et al. 2003

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The growth factor heregulin (HRG), expressed in about 30% of breast cancer tumors, activates the erbB-2 receptor via induction of heterodimeric complexes of erbB-2 with erbB-3 or erbB-4. HRG induces tumorigenicity and metastasis of breast cancer cells. Our investigation into whether HRG is a factor likely to promote tumor formation independently of erbB-2 overexpression concludes that blockage of HRG expression suppresses the aggressive phenotype of MDA-MB-231 breast cancer cells by inhibiting cell proliferation, preventing anchorageindependent growth, and suppressing the invasive potential of the cells in vitro. More importantly, we observed a marked reduction in tumor formation, tumor size, and a lack of metastasis in vivo. These studies were achieved by blocking HRG expression in MDA-MB-231 cells using an HRG antisense cDNA. In the search for the mechanism by which blockage of HRG reverts this aggressive phenotype, we discovered that the cells in which HRG is blocked exhibit a marked decrease in erbB activation and a significant reduction in MMP-9 activity, demonstrating a direct causal role in HRG induction of tumorigenicity. Our study is the first report and serves as a proof of the concept that HRG is a key promoter of breast cancer tumorigenicity and metastasis independently of erbB-2 overexpression and should be deemed a potential target in developing therapies for breast cancer.

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Heregulin regulates the actin cytoskeleton and promotes invasive properties in breast cancer cell lines.

Cited by 54 publications

References 0 publications

The ERBB3 receptor in cancer and cancer gene therapy

The ERBB3 receptor in cancer and cancer gene therapy

Activation of AKT/PKB in breast cancer predicts a worse outcome among endocrine treated patients

Blockage of heregulin expression inhibits tumorigenicity and metastasis of breast cancer

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