Abstract SY02-02: Interaction of MMPs with oncogenic signaling: Disruption of dynamic reciprocity and tissue polarity

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Abstract Whether or not epithelial cells organize into three-dimensional structures defines their normal or invasive and malignant status. In a model of human breast morphogenesis, we have shown that inhibiting key signaling pathways in breast cancer cells leads to phenotypic reversion of the malignant cells. Using intact architecture or invasive behavior as an endpoint, we report that in all cases, signaling through Raf/MEK/ERK disrupts tissue polarity via MMP9 activity. Induction of Raf or activation of an engineered functionally inducible MMP9 in nonmalignant cells leads to loss of tissue polarity and reinitiates proliferation. Conversely, inhibition of Raf or MMP9 with small molecule inhibitors or shRNAs restores the ability of cancer cells to form polarized quiescent structures. Silencing MMP9 expression reduces tumor growth dramatically in a murine xenograft model. LC-MS/MS analysis comparing secreted proteins from nonmalignant cells – with or without active MMP9 – reveals laminin 111 (LN1) as a prominent target of MMP9. LN1 is shown to be necessary for acinar morphogenesis; thus its degradation by MMP9 provides the molecular mechanism by which tissue polarity is lost and growth and invasion reinitiated. These findings underscore the essential dynamic reciprocity between ECM integrity, tissue polarity, and suppression of Raf/MEK/ERK and MMP9 activities: the correct balance is essential to homeostasis, whereas imbalance leads to malignant progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY02-02. doi:10.1158/1538-7445.AM2011-SY02-02

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