Abstract
Inflammatory breast cancer (IBC) is an aggressive form of breast cancer with a 5-year disease-free survival of less than 45%. Little is known about the genetic alterations that result in IBC. In our previous work, we found that WISP3 was specifically lost in human IBC tumors when compared to stage-matched, non-IBC tumors. We hypothesize that WISP3 has tumor suppressor function in the breast and that it may be a key genetic alteration that contributes to the unique IBC phenotype. The full-length WISP3 cDNA was sequenced and cloned into an expression vector. The resulting construct was introduced in to the SUM149 cell line that was derived from a patient with IBC and lacks WISP3 expression. In soft agar, stable WISP3 transfectants formed significantly fewer colonies than the controls. Stable WISP3 transfectants lost their ability to invade and had reduced angiogenic potential. WISP3 transfection was effective in suppressing in vivo tumor growth in nude mice. Mice bearing WISP3 expressing tumors had a significantly longer survival than those with vector-control transfectant tumors. Our data demonstrate that WISP3 acts as a tumor suppressor gene in the breast. Loss of WISP3 expression contributes to the phenotype of IBC by regulating tumor cell growth, invasion and angiogenesis.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Breast Neoplasms / genetics*
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Breast Neoplasms / pathology
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CCN Intercellular Signaling Proteins
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Carcinoma / genetics*
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Carcinoma / pathology
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Cell Cycle
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Cell Cycle Proteins / biosynthesis
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Cell Cycle Proteins / genetics
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclin-Dependent Kinase Inhibitor p27
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Cyclins / biosynthesis
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Cyclins / genetics
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DNA, Complementary / genetics
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Female
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Genes, Tumor Suppressor*
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Growth Substances / biosynthesis
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Growth Substances / genetics
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Humans
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Inflammation
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Insulin-Like Growth Factor Binding Proteins
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Mice
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Mice, Nude
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology*
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Neoplasm Transplantation
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Neovascularization, Pathologic / genetics
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Recombinant Fusion Proteins / physiology
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Transfection
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Transplantation, Heterologous
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Tumor Cells, Cultured / metabolism
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Tumor Cells, Cultured / transplantation
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Tumor Suppressor Proteins / biosynthesis
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Tumor Suppressor Proteins / genetics
Substances
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CCN Intercellular Signaling Proteins
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CCN6 protein, human
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CDKN1A protein, human
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Cdkn1a protein, mouse
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Cdkn1b protein, mouse
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Cell Cycle Proteins
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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DNA, Complementary
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Growth Substances
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Insulin-Like Growth Factor Binding Proteins
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Neoplasm Proteins
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Recombinant Fusion Proteins
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Tumor Suppressor Proteins
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Cyclin-Dependent Kinase Inhibitor p27