Profilin-1 downregulation has contrasting effects on early vs late steps of breast cancer metastasis

Z. Ding, M. Joy, R. Bhargava, M. Gunsaulus, N. Lakshman, M. Miron-Mendoza, M. Petroll, J. Condeelis, A. Wells, P. Roy

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Profilin1 (Pfn1), a ubiquitously expressed actin-binding protein, has an indispensable role in migration and proliferation of normal cells. Seemingly contrary to its essential cellular functions, Pfn1's expression is downregulated in breast cancer, the significance of which is unclear. In this study, expression profiling of Pfn1 in human breast cancer specimens correlates lower Pfn1 expression levels with propensity to metastasize. Xenograft experiments further establish a causal relationship between loss of Pfn1 expression and increased dissemination of breast cancer cells (BCCs) from the primary mammary tumor. BCCs exhibit a hyperinvasive phenotype (marked by matrix metalloproteinase-9 upregulation, faster invasion through collagen matrix) and acquire increased proficiency to transmigrate through endothelial barrier (an obligatory step for vascular dissemination) when Pfn1 expression is suppressed. In Pfn1-deficient cells, hyperinvasiveness involves a phosphatidylinositol 3-kinase-PI(3,4)P 2 signaling axis while augmented transendothelial migration occurs in a vascular endothelial growth factor-dependent manner. Contrasting these dissemination promoting activities, loss of Pfn1, however, dramatically inhibits metastatic outgrowth of disseminated BCCs, suggesting that Pfn1 has a key role in the metastatic colonization process. In summary, this study shows that Pfn1 has a dichotomous role in early vs late steps of breast cancer metastasis.

Original languageEnglish (US)
Pages (from-to)2065-2074
Number of pages10
JournalOncogene
Volume33
Issue number16
DOIs
StatePublished - Apr 17 2014

Fingerprint

Profilins
Down-Regulation
Breast Neoplasms
Neoplasm Metastasis
Phosphatidylinositol 3-Kinase
Transendothelial and Transepithelial Migration
Microfilament Proteins
Matrix Metalloproteinase 9
Heterografts
Vascular Endothelial Growth Factor A
Blood Vessels
Up-Regulation
Collagen
Cell Proliferation
Phenotype

Keywords

  • breast cancer
  • metastasis
  • profilin-1

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Ding, Z., Joy, M., Bhargava, R., Gunsaulus, M., Lakshman, N., Miron-Mendoza, M., ... Roy, P. (2014). Profilin-1 downregulation has contrasting effects on early vs late steps of breast cancer metastasis. Oncogene, 33(16), 2065-2074. https://doi.org/10.1038/onc.2013.166

Profilin-1 downregulation has contrasting effects on early vs late steps of breast cancer metastasis. / Ding, Z.; Joy, M.; Bhargava, R.; Gunsaulus, M.; Lakshman, N.; Miron-Mendoza, M.; Petroll, M.; Condeelis, J.; Wells, A.; Roy, P.

In: Oncogene, Vol. 33, No. 16, 17.04.2014, p. 2065-2074.

Research output: Contribution to journalArticle

Ding, Z, Joy, M, Bhargava, R, Gunsaulus, M, Lakshman, N, Miron-Mendoza, M, Petroll, M, Condeelis, J, Wells, A & Roy, P 2014, 'Profilin-1 downregulation has contrasting effects on early vs late steps of breast cancer metastasis', Oncogene, vol. 33, no. 16, pp. 2065-2074. https://doi.org/10.1038/onc.2013.166
Ding Z, Joy M, Bhargava R, Gunsaulus M, Lakshman N, Miron-Mendoza M et al. Profilin-1 downregulation has contrasting effects on early vs late steps of breast cancer metastasis. Oncogene. 2014 Apr 17;33(16):2065-2074. https://doi.org/10.1038/onc.2013.166
Ding, Z. ; Joy, M. ; Bhargava, R. ; Gunsaulus, M. ; Lakshman, N. ; Miron-Mendoza, M. ; Petroll, M. ; Condeelis, J. ; Wells, A. ; Roy, P. / Profilin-1 downregulation has contrasting effects on early vs late steps of breast cancer metastasis. In: Oncogene. 2014 ; Vol. 33, No. 16. pp. 2065-2074.
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