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Integrin ?3?1 can function to promote spontaneous metastasis and lung colonization of invasive breast carcinoma.

ABSTRACT: Significant evidence implicates ?3?1 integrin in promoting breast cancer tumorigenesis and metastasis-associated cell behaviors in vitro and in vivo. However, the extent to which ?3?1 is actually required for breast cancer metastasis remains to be determined. We used RNA interference to silence ?3 integrin expression by approximately 70% in 4T1 murine mammary carcinoma cells, a model of aggressive, metastatic breast cancer. Loss of ?3 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 ?3-silenced (?3si) cells, suggesting that critical, ?3-dependent events at the metastatic site could account for much of ?3?1's contribution to metastasis in this model. Reexpressing ?3 in the ?3si 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 ?3. Parental, ?3si, and ?3-rescued cells, all secreted abundant laminin ?5 (LAMA5), an ?3?1 integrin ligand, suggesting that loss of ?3 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 ?3 integrin and LAMA5 are both overexpressed.?3 integrin or downstream effectors may be potential therapeutic targets in disseminated breast cancers, especially when laminin ?5 or other ?3 integrin ligands are also over-expressed.

SUBMITTER: Zhou B

PROVIDER: S-EPMC3947021 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Integrin α3β1 can function to promote spontaneous metastasis and lung colonization of invasive breast carcinoma.

Zhou Bo B Gibson-Corley Katherine N KN Herndon Mary E ME Sun Yihan Y Gustafson-Wagner Elisabeth E Teoh-Fitzgerald Melissa M Domann Frederick E FE Henry Michael D MD Stipp Christopher S CS

Molecular cancer research : MCR 20130903 1

<h4>Unlabelled</h4>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 ...[more]

PMID: 24002891

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Project description:Studies in xenograft models and experimental models of metastasis have implicated several beta3 integrin-expressing cell populations, including endothelium, platelets and osteoclasts, in breast tumor progression. Since orthotopic human xenograft models of breast cancer are poorly metastatic to bone and experimental models bypass the formation of a primary tumor, however, the precise contribution of tumor-specific alphavbeta3 to the spontaneous metastasis of breast tumors from the mammary gland to bone remains unclear.We used a syngeneic orthotopic model of spontaneous breast cancer metastasis to test whether exogenous expression of alphavbeta3 in a mammary carcinoma line (66cl4) that metastasizes to the lung, but not to bone, was sufficient to promote its spontaneous metastasis to bone from the mammary gland. The tumor burden in the spine and the lung following inoculation of alphavbeta3-expressing 66cl4 (66cl4beta3) tumor cells or control 66cl4pBabe into the mammary gland was analyzed by real-time quantitative PCR. The ability of these cells to grow and form osteolytic lesions in bone was determined by histology and tartrate-resistant acid phosphatase staining of bone sections following intratibial injection of tumor cells. The adhesive, migratory and invasive properties of 66cl4pBabe and 66cl4beta3 cells were evaluated in standard in vitro assays.The 66cl4beta3 tumors showed a 20-fold increase in metastatic burden in the spine compared with 66cl4pBabe. A similar trend in lung metastasis was observed. alphavbeta3 did not increase the proliferation of 66cl4 cells in vitro or in the mammary gland in vivo. Similarly, alphavbeta3 is not required for the proliferation of 66cl4 cells in bone as both 66cl4pBabe and 66cl4beta3 proliferated to the same extent when injected directly into the tibia. 66cl4beta3 tumor growth in the tibia, however, increased osteoclast recruitment and bone resorption compared with 66cl4 tumors. Moreover, alphavbeta3 increased 66cl4 tumor cell adhesion and alphavbeta3-dependent haptotactic migration towards bone matrix proteins, as well as their chemotactic response to bone-derived soluble factors in vitro.These results demonstrate for the first time that tumor-specific alphavbeta3 contributes to spontaneous metastasis of breast tumors to bone and suggest a critical role for this receptor in mediating chemotactic and haptotactic migration towards bone factors.

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Integrin ?3?1 can function to promote spontaneous metastasis and lung colonization of invasive breast carcinoma.

Publications

Integrin α3β1 can function to promote spontaneous metastasis and lung colonization of invasive breast carcinoma.

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