Journal article
Integrin α3β1 can function to promote spontaneous metastasis and lung colonization of invasive breast carcinoma
Molecular cancer research, Vol.12(1), pp.143-154
01/2014
DOI: 10.1158/1541-7786.MCR-13-0184
PMCID: PMC3947021
PMID: 24002891
Abstract
Significant evidence implicates α3β1 integrin in promoting breast cancer tumorigenesis and metastasis-associated cell behaviors in vitro and in vivo. However, the extent to which α3β1 is actually required for breast cancer metastasis remains to be determined. We used RNA interference to silence α3 integrin expression by approximately 70% in 4T1 murine mammary carcinoma cells, a model of aggressive, metastatic breast cancer. Loss of α3 integrin reduced adhesion, spreading, and proliferation on laminin isoforms, and modestly reduced the growth of orthotopically implanted cells. However, spontaneous metastasis to lung was strikingly curtailed. Experimental lung colonization after tail vein injection revealed a similar loss of metastatic capacity for the α3-silenced (α3si) cells, suggesting that critical, α3-dependent events at the metastatic site could account for much of α3β1's contribution to metastasis in this model. Reexpressing α3 in the α3si cells reversed the loss of metastatic capacity, and silencing another target, the small GTPase RhoC, had no effect, supporting the specificity of the effect of silencing α3. Parental, α3si, and α3-rescued cells, all secreted abundant laminin α5 (LAMA5), an α3β1 integrin ligand, suggesting that loss of α3 integrin might disrupt an autocrine loop that could function to sustain metastatic growth. Analysis of human breast cancer cases revealed reduced survival in cases where α3 integrin and LAMA5 are both overexpressed.
α3 integrin or downstream effectors may be potential therapeutic targets in disseminated breast cancers, especially when laminin α5 or other α3 integrin ligands are also over-expressed.
Details
- Title: Subtitle
- Integrin α3β1 can function to promote spontaneous metastasis and lung colonization of invasive breast carcinoma
- Creators
- Bo Zhou - Department of Biology, University of Iowa, Iowa City, IA, 52242 USAKatherine N Gibson-Corley - Department of Pathology, University of Iowa, Iowa City, IA, 52242 USAMary E Herndon - Department of Biology, University of Iowa, Iowa City, IA, 52242 USAYihan Sun - Department of Biology, University of Iowa, Iowa City, IA, 52242 USAElisabeth Gustafson-Wagner - Department of Biology, University of Iowa, Iowa City, IA, 52242 USAMelissa Teoh-Fitzgerald - Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa, Iowa City, IA, 52242 USAFrederick E Domann - Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, 52242 USAMichael D Henry - Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, 52242 USAChristopher S Stipp - Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, 52242 USA
- Resource Type
- Journal article
- Publication Details
- Molecular cancer research, Vol.12(1), pp.143-154
- Publisher
- United States
- DOI
- 10.1158/1541-7786.MCR-13-0184
- PMID
- 24002891
- PMCID
- PMC3947021
- ISSN
- 1541-7786
- eISSN
- 1557-3125
- Grant note
- R01 CA115438 / NCI NIH HHS P30 CA086862 / NCI NIH HHS R01 CA130916 / NCI NIH HHS R01 CA136664 / NCI NIH HHS
- Language
- English
- Date published
- 01/2014
- Academic Unit
- Molecular Physiology and Biophysics; Pathology; Surgery; Biology; Radiation Oncology; Urology; Ophthalmology and Visual Sciences
- Record Identifier
- 9984047718102771
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