Integrin a3b1 can function to promote spontaneous metastasis and lung colonization of invasive breast carcinoma

Abstract

Significant evidence implicatesa3b1 integrin in promoting breast cancer tumorigenesis and metastasis-associated cell behaviors in vitro and in vivo. However, the extent to whicha3b1 is actually required for breast cancer metastasis remains to be determined. We used RNA interference to silence a3 integrin expression by approximately 70% in 4T1 murine mammary carcinoma cells, a model of aggressive, metastatic breast cancer. Loss of a3 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 a3-silenced (a3si) cells, suggesting that critical, a3-dependent events at the metastatic site could account for much of a3b10s contribution to metastasis in this model. Reexpressinga3 in thea3si 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 a3. Parental, a3si, and a3-rescued cells, all secreted abundant laminin a5 (LAMA5), an a3b1 integrin ligand, suggesting that loss of a3 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 a3 integrin and LAMA5 are both overexpressed. © 2013 AACR.