Regulation of Snail in breast cancer progression and metastasis

Basal-like breast cancer (BLBC) associates with an aggressive clinical history, development of recurrence, distant metastasis, shorter survival, and usually occurs in young women. It intrinsically possesses many epithelial-mesenchymal transition (EMT) characteristics and stem cell-like features, suggesting that activation of EMT program generates high-grade invasive cells with stem cell-like features in BLBC. Our long-term goal is to identify the intrinsic factors within tumor cells as well as extrinsic signals from tumor microenvironments that regulate EMT and identify proteins that may serve as druggable targets for treating this deadly disease. In the last several years, we have systematically studied the role of Snail and the molecular mechanism by which Snail represses E-cadherin expression in BLBC. Our study clearly indicates that Snail is one of the key intrinsic factors within tumor cells responsible for EMT; our study also implies that the inflammatory tumor microenvironment provides an extrinsic signal for EMT. However, how the extrinsic tumor milieu of BLBC is initiated and built up, despite its paramount importance, remains unaddressed. Recently, we found that X-box binding protein (XBP1) expression is significantly reduced in BLBC from human breast tumor samples and mouse breast cancer tissues. Snail suppressed XBP1 expression and resulted in a significant upregulation of CCL2, a major chemokine for TAMs and lymphocytes. XBP1 is a key molecule in the most conserved “unfolded-protein response” (UPR) signaling pathway that cells use to cope with environmental and cellular stresses in endoplasmic reticulum (ER). Loss of XBP1 results in “unresolved ER stress”, which signals endogenous cellular injury, triggering leukocyte infiltration, and a significant boost of inflammatory responses in target tissues. Thus, we hypothesize that the loss of XBP1 by Snail-mediated repression ignites an “inside out” signal for recruiting TAMs and lymphocytes, which establish an inflammatory/wound microenvironment to further boost EMT and cultivate stem cell-like traits in BLBC by providing additional cytokines and growth factors. The objective of this proposal is to characterize the repression of XBP1 by Snail and explore therapeutic interventions that will disrupt this vicious cycle and thereby restore ER homeostasis in BLBC. Guided by strong preliminary data, we will test this hypothesis by pursuing three specific aims: (1) to determine the molecular mechanisms for Snail-mediated XBP1 repression in BLBC; (2) to delineate why loss of XBP1 enhances inflammation in BLBC; and (3) to elucidate the functional roles of XBP1 in vivo. Our proposal is innovative and significant, because it will not only open a new paradigm that significantly affects our views on the recruitment of infiltrating immune cells by tumor cells in the progression and metastasis of breast cancer but will also lay groundwork for developing new therapeutic strategies against this disease.