The α2β1 integrin is a metastasis suppressor in mouse models and human cancer
Norma E. Ramirez, Zhonghua Zhang, Aasakiran Madamanchi, Kelli L. Boyd, Lynda D. O’Rear, Abudi Nashabi, Zhengzi Li, William D. Dupont, Andries Zijlstra, Mary M. Zutter
Norma E. Ramirez, Zhonghua Zhang, Aasakiran Madamanchi, Kelli L. Boyd, Lynda D. O’Rear, Abudi Nashabi, Zhengzi Li, William D. Dupont, Andries Zijlstra, Mary M. Zutter
View: Text | PDF
Research Article Oncology

The α2β1 integrin is a metastasis suppressor in mouse models and human cancer

Abstract

Integrins regulate cell-cell and cell-matrix adhesion and thereby play critical roles in tumor progression and metastasis. Although work in preclinical models suggests that β1 integrins may stimulate metastasis of a number of cancers, expression of the β1 subunit alone has not been shown to be a useful prognostic indicator in human cancer patients. Here we have demonstrated that the α2β1 integrin suppresses metastasis in a clinically relevant spontaneous mouse model of breast cancer. These data are consistent with previous studies indicating high expression of α2β1 integrin in normal breast epithelium and loss of α2β1 in poorly differentiated breast cancer. They are also consistent with our systematic analysis of microarray databases of human breast and prostate cancer, which revealed that decreased expression of the gene encoding α2 integrin, but not genes encoding α1, α3, or β1 integrin, was predictive of metastatic dissemination and decreased survival. The predictive value of α2 expression persisted within both good-risk and poor-risk cohorts defined by estrogen receptor and lymph node status. Thus, the α2β1 integrin functionally inhibits breast tumor metastasis, and α2 expression may serve as an important biomarker of metastatic potential and patient survival.

Authors

Norma E. Ramirez, Zhonghua Zhang, Aasakiran Madamanchi, Kelli L. Boyd, Lynda D. O’Rear, Abudi Nashabi, Zhengzi Li, William D. Dupont, Andries Zijlstra, Mary M. Zutter

×

Figure 2

α2β1 integrin expression does not alter tumor growth in vivo.

Options: View larger image (or click on image) Download as PowerPoint
α2β1 integrin expression does not alter tumor growth in vivo. (A) Th...
(A) The rate of tumor growth over time was calculated from the regression slopes of tumor volume as a function of time, measured by calipers once a week (P > 0.86). (B) Total tumor burden in WT/Neu and α2-null/Neu mice was quantitated as the total number of tumors per mouse at the time of sacrifice and ranged from 1 to 5 tumors per animal. No significant difference between the 2 genotypes was observed for either tumor growth rates (P > 0.86) or number of tumors per mouse (P = 0.3). (C) Representative H&E-stained sections of primary mammary tumors from WT/Neu and α2-null/Neu animals. Scale bar: 200 μm. (D) Representative sections of primary WT/Neu and α2-null/Neu mammary tumors were analyzed by immunohistochemistry for Ki67 or TUNEL staining to define proliferation or apoptosis, respectively. Scale bar: 100 μm. (E and F) Number of Ki67-positive (E) or TUNEL-positive (F) cells in WT/Neu and α2-null/Neu primary mammary tumors was quantitated in 10 high-power fields. There was no significant difference between the cohorts for either Ki67-positive (P > 0.27) or TUNEL-positive (P > 0.32) cells. (G) Immunofluorescence analysis demonstrated α2β1 integrin expression (red) by tumors from WT/Neu animals, but not α2-null/Neu mice. Nuclei are stained with DAPI (blue). Scale bar: 60 μm.