Targeting interferon response genes sensitizes aromatase inhibitor resistant @entity0 cells to XXXX -induced cell @entity204 .

@entity172 @entity1 @entity17442 @entity26242 @entity589 @entity0 @entity686 @entity1488 @entity5 @entity43429 @entity37032 @entity17619 @entity3544 @entity53 @entity6897 @entity204
INTRODUCTION: @entity172 deprivation using aromatase inhibitors (AIs) is currently the standard of care for postmenopausal @entity1 with hormone receptor-positive @entity0 . Unfortunately, the majority of @entity1 treated with AIs eventually develop resistance, inevitably resulting in @entity1 relapse and, ultimately, @entity204 . The mechanism by which resistance occurs is still not completely known, however, recent studies suggest that impaired/defective interferon signaling might play a role. In the present study, we assessed the functional role of @entity17442 and @entity37032 ; two well-known interferon response genes in AI resistance. METHODS: Real-time PCR and Western blot analyses were used to assess mRNA and protein levels of @entity17442 , @entity37032 , @entity6897 , @entity17619 , and @entity26242 in AI-resistant MCF-7:5C @entity0 cells and AI-sensitive MCF-7 and T47D cells. Immunohistochemistry (IHC) staining was performed on tissue microarrays consisting of normal breast tissues, primary @entity0 , and @entity5 . Enzyme-linked immunosorbent assay was used to quantitate intracellular @entity686 level. Neutralizing antibody was used to block type 1 interferon receptor IFNAR1 signaling. Small interference RNA (siRNA) was used to knockdown @entity17442 , @entity37032 , @entity6897 , @entity17619 , @entity26242 , and @entity686 expression. RESULTS: We found that @entity17442 and @entity37032 were constitutively overexpressed in AI-resistant MCF-7:5C @entity0 and that siRNA knockdown of @entity17442 significantly inhibited the ability of the resistant cells to proliferate, migrate, and invade. Interestingly, suppression of @entity17442 significantly enhanced @entity53 -induced cell @entity204 in AI-resistant MCF-7:5C cells and markedly increased expression of @entity3544 , @entity589 , and @entity1488 in these cells. Significantly elevated level of @entity686 was detected in AI-resistant MCF-7:5C cells compared to parental MCF-7 cells and suppression of @entity686 dramatically reduced @entity17442 , @entity37032 , p- @entity6897 , and p- @entity17619 expression in the resistant cells. Lastly, neutralizing antibody against @entity43429 and knockdown of @entity6897 / @entity17619 completely suppressed @entity17442 , @entity37032 , p- @entity6897 , and p- @entity17619 expression in the resistant cells, thus confirming the involvement of the canonical @entity686 signaling pathway in driving the overexpression of @entity17442 and other interferon-stimulated genes (ISGs) in the resistant cells. CONCLUSION: Overall, these results demonstrate that constitutive overexpression of ISGs enhances the progression of @entity0 and that suppression of @entity17442 and other ISGs sensitizes AI-resistant cells to @entity172 -induced cell @entity204 .
