Abstract
<div>AbstractPurpose:<p>We evaluated the role of everolimus in the prevention of ductal carcinoma <i>in situ</i> (DCIS) to invasive ductal carcinoma (IDC) progression.</p>Experimental Design:<p>The effects of everolimus on breast cancer cell invasion, DCIS formation, and DCIS progression to IDC were investigated in a 3D cell culturing model, intraductal DCIS xenograft model, and spontaneous MMTV-Her2/neu mouse model. The effect of everolimus on matrix metalloproteinase 9 (MMP9) expression was determined with Western blotting and IHC in these models and in patients with DCIS before and after a window trial with rapamycin. Whether MMP9 mediates the inhibition of DCIS progression to IDC by everolimus was investigated with knockdown or overexpression of MMP9 in breast cancer cells.</p>Results:<p>Everolimus significantly inhibited the invasion of human breast cancer cells <i>in vitro</i>. Daily intragastric treatment with everolimus for 7 days significantly reduced the number of invasive lesions from intraductal DCIS foci and inhibited DCIS progression to IDC in the MMTV-Her2/neu mouse mammary tumor model. Mechanistically, everolimus treatment decreased the expression of MMP9 in the <i>in vitro</i> and <i>in vivo</i> models, and in breast tissues from patients with DCIS treated with rapamycin for 1 week. Moreover, overexpression of MMP9 stimulated the invasion, whereas knockdown of MMP9 inhibited the invasion of breast cancer cell–formed spheroids <i>in vitro</i> and DCIS <i>in vivo</i>. Knockdown of MMP9 also nullified the invasion inhibition by everolimus <i>in vitro</i> and <i>in vivo</i>.</p>Conclusions:<p>Targeting mTORC1 can inhibit DCIS progression to IDC via MMP9 and may be a potential strategy for DCIS or early-stage IDC therapy.</p></div>
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