Using the MCF10AT model, we show that PADI2 is highly upregulated following transform ation at both the mRNA and protein level, with highest levels in the cell line that recapitulates human comedo DCIS. Furthermore, we Nilotinib side effects show that, across a wide array of breast cancer cell lines, PADI2 is specifically overex pressed in the luminal subtype, while also being highly correlated with HER2 ERBB2 overexpression. This ob servation suggests that PADI2 may function as a bio marker for HER2 ERBB2 lesions. Lastly, our preclinical mouse xenograft study suggests that the PADI inhibitor, Cl amidine, could potentially be utilized as a therapeutic agent for the treatment of comedo DCIS tumors. Background Despite improvements in the accuracy of clinical staging for solid cancers, the survival rates for patients affected with these tumor types have improved only modestly over the last few decades.

Many solid tumors are unre sponsive to conventional therapy due to the resistance of the tumor cells to programmed cell death. The downre gulation of Bcl xL has been shown to induce apoptosis and increase chemosensitivity but resistance to chemotherapy is still observed in some cancer cells even after Bcl 2 Bcl xL inhibition. Recent reports have revealed that the overexpression of Mcl 1 compensates for the loss of the anti apoptotic function of Bcl 2 xL. A reduction in Mcl 1 significantly enhances the sensitivity of cancer cells to ABT 737 and other che motherapeutics. In addition, the forced overexpres sion of Mcl 1 in transgenic mice leads to a significantly increased incidence of B cell lymphoma.

Hence, the cumulative evidence to date suggests that Mcl 1 overex pression may function as an additional survival mechan ism that protects cancer cells against conventional therapies. Mcl 1 expression, just like Bcl xL expression, is highly induced under conditions that are conducive to survival and by differentiation signals from cytokines and growth factors. Mitogen activated protein kinase phosphatidylinositol 3 and Janus kinase sig nal transducer and activator of transcription dependent pathways have all been implicated in the stimulation of Mcl 1 transcription, acting via specific transcription factor response elements in the Mcl 1 gene promoter. However, the direct phosphorylation of Mcl 1 also plays an important role in controlling its expression and function. Mcl 1 can be phosphoryl ated in its PEST region, and thus stabilized, upon Dacomitinib ERK activation. Additionally, Mcl 1 is regulated by a subtle balance be tween ubiquitination and deubiquitination. Two E3 ligases have been implicated in Mcl 1 turnover. The first of these is Mcl 1 ubiquitinating ligase E3 which possesses a BH3 domain similar to that of proapoptotic BAK that allows it to target Mcl 1.