C-erbB-2/HER-2 upregulates fascin, an actin-bundling protein associated with cell motility, in human breast cancer cell lines

Axel F Grothey, Rintaro Hashizume, Hong Ji, Benjamin E. Tubb, Charles W. Patrick, Dihua Yu, Erin E. Mooney, Pierre D. McCrea

Research output: Contribution to journalArticle

95 Citations (Scopus)

Abstract

The over-expression of c-erbB-2/ HER-2, a receptor tyrosine kinase, correlates with poor prognosis in patients with breast and ovarian cancer. In the human breast cancer cell line, MDA-MB-435, c-erbB-2 over-expression results in increased chemoinvasion and higher metastatic properties in nude mice. However, the mechanisms by which c-erbB-2 increases the malignant potential of cells remains unclear. We have determined that over-expression of c-erbB-2 in MDA-MB-435 cells, and in some additional breast cancer cell lines, is associated with graphic increases in mRNA and protein levels of the actin bundling protein fascin. Heightened fascin expression has been observed in other systems to result in greatly increased cell motility, and indeed, our work employing semi-automated time-lapse microscopy demonstrates that MDA-MB-435 cells over-expressing c-erbB-2 exhibit significantly heightened cellular dynamics and locomotion, while visualization of bundled microfilaments within fixed cells revealed enhanced formation of dendritic-like processes microspikes and other dynamic actin based structures. To address the means by which c-erbB-2 over-expression might result in elevated fascin levels, we identified multiple perfect match TCF and NF-κB consensus sites in fascin's promoter and first intron, which a appeared consistent with the greater endogenous transcriptional activities of TCF and NF-κB in c-erbB-2 over-expressing MDA-MB-435 cells. While such transcriptional modulation may occur in the context of the intact gene/chromatin, subsequent tests using reporter constructs did not support involvement of these signaling pathways. In conclusion, highly increased fascin levels were observed in MDA-MB-435 over-expressing c-erbB-2, likely contributing to these cells' altered actin dynamics, and increased cell motility and malignancy. Studies in progress aim to discern the means by which c-erbB-2 over-expression leads to transcriptional activation of the fascin gene.

Original languageEnglish (US)
Pages (from-to)4864-4875
Number of pages12
JournalOncogene
Volume19
Issue number42
StatePublished - Oct 5 2000
Externally publishedYes

Fingerprint

Cell Movement
Actins
Up-Regulation
Breast Neoplasms
Cell Line
Proteins
Receptor Protein-Tyrosine Kinases
Locomotion
Actin Cytoskeleton
Nude Mice
Ovarian Neoplasms
Introns
Transcriptional Activation
Genes
Chromatin
fascin
Microscopy
Messenger RNA
Neoplasms

Keywords

  • Actin
  • Breast cancer
  • C-erbB-2
  • Cell motility
  • Fascin

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Grothey, A. F., Hashizume, R., Ji, H., Tubb, B. E., Patrick, C. W., Yu, D., ... McCrea, P. D. (2000). C-erbB-2/HER-2 upregulates fascin, an actin-bundling protein associated with cell motility, in human breast cancer cell lines. Oncogene, 19(42), 4864-4875.

C-erbB-2/HER-2 upregulates fascin, an actin-bundling protein associated with cell motility, in human breast cancer cell lines. / Grothey, Axel F; Hashizume, Rintaro; Ji, Hong; Tubb, Benjamin E.; Patrick, Charles W.; Yu, Dihua; Mooney, Erin E.; McCrea, Pierre D.

In: Oncogene, Vol. 19, No. 42, 05.10.2000, p. 4864-4875.

Research output: Contribution to journalArticle

Grothey, AF, Hashizume, R, Ji, H, Tubb, BE, Patrick, CW, Yu, D, Mooney, EE & McCrea, PD 2000, 'C-erbB-2/HER-2 upregulates fascin, an actin-bundling protein associated with cell motility, in human breast cancer cell lines', Oncogene, vol. 19, no. 42, pp. 4864-4875.
Grothey AF, Hashizume R, Ji H, Tubb BE, Patrick CW, Yu D et al. C-erbB-2/HER-2 upregulates fascin, an actin-bundling protein associated with cell motility, in human breast cancer cell lines. Oncogene. 2000 Oct 5;19(42):4864-4875.
Grothey, Axel F ; Hashizume, Rintaro ; Ji, Hong ; Tubb, Benjamin E. ; Patrick, Charles W. ; Yu, Dihua ; Mooney, Erin E. ; McCrea, Pierre D. / C-erbB-2/HER-2 upregulates fascin, an actin-bundling protein associated with cell motility, in human breast cancer cell lines. In: Oncogene. 2000 ; Vol. 19, No. 42. pp. 4864-4875.
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