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. 2010 Aug 31;107(35):15559-64.
doi: 10.1073/pnas.1003034107. Epub 2010 Aug 16.

beta1-integrin is dispensable for the induction of ErbB2 mammary tumors but plays a critical role in the metastatic phase of tumor progression

L Huck  1 , S M Pontier, D M Zuo, W J Muller
Affiliations

beta1-integrin is dispensable for the induction of ErbB2 mammary tumors but plays a critical role in the metastatic phase of tumor progression

L Huck et al. Proc Natl Acad Sci U S A. .

Abstract

Cross-talk between integrin receptors and activated growth factor receptors has been hypothesized to play a critical role in the initiation and progression of cancer. Despite in vitro evidence documenting the important role of integrin receptors in the regulation of cancer cell proliferation, the relative contribution of the integrin receptors to the initiation and progression of tumors remains unclear. Previous studies with a polyomavirus middle T mammary tumor model have indicated that targeted disruption of beta1-integrin in the mammary glands of these mice completely blocks tumor induction. To further explore the general significance of these observations, we have crossed these conditional beta1-integrin strains to a strain of mice carrying mouse mammary tumor virus/activated erbB2 (herein referred to as the NIC strain). In contrast to the tumor induction block in the polyomavirus middle T model, tumor onset in the beta1-integrin-deficient NIC mice was delayed by only 30 d and was 100% penetrant. This modest effect on tumor induction was not a result of inefficient excision, as all tumors were confirmed as beta1-integrin-null. Animals bearing beta1-integrin-deficient ErbB2 tumors exhibited significantly reduced tumor volume, which was associated with increased tumor cell apoptosis and a reduction in tumor angiogenesis. In addition, beta1-integrin-deficient tumors were compromised in their capacity to metastasize to the lung, a deficiency associated with abrogation of adhesion signaling. Taken together, these observations suggest that, although beta1-integrin is dispensable for the initiation of ErbB2 tumor induction, it plays a critical role in metastatic phase of tumor progression.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
β1-Integrin deletion delays tumor onset. (A) Schematic representation of the MMTV/activated erbB2 transgenic mice (NIC strain) and of the β1-integrinflox allele. (B) Kaplan-Meier analysis of tumor onsets. Control NIC β1wt/wt mice versus NIC β1f/wt versus NIC β1f/f (P = 0.0004). Median tumor onset values are indicated. The P values were calculated from a two-tailed Student t test. (C) β1-Integrin expression in the mammary breast tumor was assessed for NIC β1wt/wt or NIC β1f/f mice by immunoblotting.
Fig. 2.
Fig. 2.
β1-Integrin–deleted tumors have reduced metastasis. (A) Average total tumor burden per animal (in cm3) for NIC β1wt/wt, NIC β1f/wt, or NIC β1f/f mice that have developed tumors. The error bars represent the SE for 19 NIC β1wt/wt, 14 NIC β1f/wt, or 17 NIC β1f/f mice. The indicated P value was calculated from a two-tailed Student t test. (B) Percentage of mice from FVB primary genotype (as indicated) that developed lung metastatic lesions. (C) Average number of metastatic lesions per lung in mice from B. The indicated P value was calculated from a two-tailed Student t test. Error bars represent SE for 11 NIC β1wt/wt, 12 NIC β1f/wt, or 17 NIC β1f/f mice. (D) Cells (0.5 million) from dissociated NIC β1wt/wt or NIC β1f/f primary tumors were injected in the tail vein of Ncr mice. (Upper) H&E-stained sections of the lungs collected 8 wk after injection. (Scale bar: 1 mm.) (Lower) Average lung area that is covered by metastatic lesions in percentage. The indicated P value was calculated from a two-tailed Student t test. Error bars represent SE for each genotype (n = 4).
Fig. 3.
Fig. 3.
β1-Integrin deletion decreases tumor growth by impairing cell survival. (A) Proliferation was assessed by immunohistochemistry staining on sections of paraffin-embedded mammary tumors with Ki67 antibody. (Scale bar: 50 μm.) The bar graph (Lower) represents the percentage of Ki67-positive cells. Error bars represent the SE of cells counted in at least three mammary tumors. (B) TUNEL-stained sections of paraffin-embedded mammary tumors of the indicated genotype. (Scale bar: 50 μm.) Apoptotic cells appear brown (arrows). The bar graph (Lower) represents the percentage of TUNEL-positive cells (Left) and the Ki67/TUNEL ratio (Right). Error bars represent SE of cells counted in at least three mammary tumors. The indicated P values were calculated from a two-tailed Student t test.
Fig. 4.
Fig. 4.
β1-Integrin–deleted tumors exhibit impaired vascularization. (A) Immunohistochemistry staining of paraffin-embedded mammary tumors with an antibody directed against the endothelial-cell marker CD31. (Scale bar: 50 μm.) (B) (Upper) Percentage of CD31-positive cells for the indicated genotype. (Lower) Average area per vessel in square millimeters. Error bars represent SE of cells counted for at least three mammary tumors. The indicated P values were obtained from a two-tailed Student t test.
Fig. 5.
Fig. 5.
Loss of β1-integrin impairs signaling. (A) Activation levels of protein of the c-Src pathway (as indicated) in primary tumor lysate from the indicated genotype addressed by immunoblotting. (B) Activation and total levels of EGFR in primary tumor lysate of the indicated genotype tested by immnublotting.
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References

    1. Grasso AW, et al. ErbB kinases and NDF signaling in human prostate cancer cells. Oncogene. 1997;15:2705–2716. - PubMed
    1. Guo W, et al. Beta 4 integrin amplifies ErbB2 signaling to promote mammary tumorigenesis. Cell. 2006;126:489–502. - PubMed
    1. Kren A, et al. Increased tumor cell dissemination and cellular senescence in the absence of beta1-integrin function. EMBO J. 2007;26:2832–2842. - PMC - PubMed
    1. White DE, et al. Targeted disruption of beta1-integrin in a transgenic mouse model of human breast cancer reveals an essential role in mammary tumor induction. Cancer Cell. 2004;6:159–170. - PubMed
    1. Park CC, Zhang HJ, Yao ES, Park CJ, Bissell MJ. Beta1 integrin inhibition dramatically enhances radiotherapy efficacy in human breast cancer xenografts. Cancer Res. 2008;68:4398–4405. - PMC - PubMed

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