Integrin α3β1 Represses Reelin Expression in Breast Cancer Cells to Promote Invasion

Simple Summary Breast cancer remains the second leading cause of cancer-related deaths in women, and about 1 in 8 women in the United States develops invasive breast cancer in her lifetime. Integrin alpha 3 beta 1 has been linked to breast cancer progression, but mechanisms whereby it promotes tumor invasion remain unclear. The goal of our study was to determine how alpha 3 beta 1 drives invasion, towards exploiting this integrin as a therapeutic target for breast cancer. We found that alpha 3 beta 1 represses the expression of Reelin, a secreted glycoprotein that inhibits invasion and for which loss of expression is associated with poor prognosis in breast cancer. We also show that increased Reelin expression following RNAi-mediated suppression of alpha 3 beta 1 causes a significant decrease in breast cancer cell invasion. Our findings demonstrate a critical role for alpha 3 beta 1 in promoting cell invasion through repression of Reelin, highlighting the potential value of this integrin as a therapeutic target for breast cancer. Integrin alpha 3 beta 1, a cell adhesion receptor for certain laminins, is known to promote breast tumor growth and invasion. Our previous gene microarray study showed that the RELN gene, which encodes the extracellular glycoprotein Reelin, was upregulated in alpha 3 beta 1-deficient (i.e., alpha 3 knockdown) MDA-MB-231 cells. In breast cancer, reduced RELN expression is associated with increased invasion and poor prognosis. In this study we demonstrate that alpha 3 beta 1 represses RELN expression to enhance breast cancer cell invasion. RELN mRNA was significantly increased upon RNAi-mediated alpha 3 knockdown in two triple-negative breast cancer cell lines, MDA-MB-231 and SUM159. Modulation of baseline Reelin levels altered invasive potential, where enhanced Reelin expression in MDA-MB-231 cells reduced invasion, while RNAi-mediated suppression of Reelin in SUM159 cells increased invasion. Moreover, treatment of alpha 3 beta 1-expressing MDA-MB-231 cells with culture medium that was conditioned by alpha 3 knockdown MDA-MB-231 cells led to decreased invasion. RNAi-mediated suppression of Reelin in alpha 3 knockdown MDA-MB-231 cells mitigated this effect of conditioned-medium, identifying secreted Reelin as an inhibitor of cell invasion. These results demonstrate a novel role for alpha 3 beta 1 in repressing Reelin in breast cancer cells to promote invasion, supporting this integrin as a potential therapeutic target.