Abstract |
Although loss of the mannose 6- phosphate/ insulin-like growth factor-II receptor (M6P/IGF-IIR) in breast cancer is believed to play a role in tumorigenesis, it has not been demonstrated that M6P/IGF-IIR loss is sufficient to confer a malignant phenotype in an untransformed cell. We investigated the impact of M6P/IGF-IIR silencing using phenotypically normal (MCF-10A) and oncogenically transformed (MCF-10T, the c-Ha-ras transformed derivative of MCF-10A) human breast epithelial cell lines as model systems. In both cell lines, silencing of M6P/IGF-IIR increased cell proliferation and motility, with the effects being more pronounced in MCF-10A cells. Although anchorage-independent growth was increased by M6P/IGF-IIR silencing in MCF-10T cells, MCF-10A cells did not acquire the ability to grow in soft agar. Conversely, reduced M6P/IGF-IIR expression increased the invasive potential of MCF-10A cells, but did not enhance the already high rate of invasion of MCF-10T cells. M6P/IGF-IIR silencing had no effect on basal or IGF-II-stimulated IGF-I receptor (IGF-IR) or AKT phosphorylation in either cell line, but both were abrogated by IGF-IR kinase inhibition, which also reduced the stimulatory effect of M6P/IGF-IIR silencing on proliferation under basal and IGF-II-stimulated conditions in both cell lines. However, cell motility was neither stimulated by IGF-II nor reduced by IGF-IR inhibition, suggesting that potentiation of specific tumorigenic features in response to M6P/IGF-IIR silencing involves IGF-II- dependent and -independent mechanisms. Collectively, these data suggest that M6P/IGF-IIR silencing alone is insufficient to confer a tumorigenic phenotype, but can enhance tumorigenicity in an already transformed cell.
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Authors | Nicole J Caixeiro, Janet L Martin, Carolyn D Scott |
Journal | International journal of cancer
(Int J Cancer)
Vol. 133
Issue 11
Pg. 2542-50
(Dec 01 2013)
ISSN: 1097-0215 [Electronic] United States |
PMID | 23686499
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2013 UICC. |
Chemical References |
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Topics |
- Breast
(cytology, metabolism)
- Breast Neoplasms
(genetics, pathology)
- Cell Line
- Cell Transformation, Neoplastic
(genetics)
- Epithelial Cells
(metabolism, pathology)
- Female
- Gene Expression Regulation, Neoplastic
- Gene Silencing
- Humans
- Receptor, IGF Type 2
(antagonists & inhibitors, genetics, metabolism)
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