Raina, DeepakUchida, YasumitsuKharbanda, AkritiRajabi, HasanPanchamoorthy, GovindJin, CainingKharbanda, SurenderScaltriti, MaurizioBaselga, JoseKufe, Donald2015-01-052014Raina, Deepak, Yasumitsu Uchida, Akriti Kharbanda, Hasan Rajabi, Govind Panchamoorthy, Caining Jin, Surender Kharbanda, Maurizio Scaltriti, Jose Baselga, and Donald Kufe. 2014. “TARGETING THE MUC1-C ONCOPROTEIN DOWNREGULATES HER2 ACTIVATION AND ABROGATES TRASTUZUMAB RESISTANCE IN BREAST CANCER CELLS.” Oncogene 33 (26): 3422-3431. doi:10.1038/onc.2013.308. http://dx.doi.org/10.1038/onc.2013.308.0950-9232http://nrs.harvard.edu/urn-3:HUL.InstRepos:13581247Patients with HER2 positive breast cancer often exhibit intrinsic or acquired resistance to trastuzumab treatment. The transmembrane MUC1-C oncoprotein is aberrantly overexpressed in breast cancer cells and associates with HER2. The present studies demonstrate that silencing MUC1-C in HER2-overexpressing SKBR3 and BT474 breast cancer cells results in downregulation of constitutive HER2 activation. Moreover, treatment with the MUC1-C inhibitor, GO-203, was associated with disruption of MUC1-C/HER2 complexes and decreases in tyrosine phosphorylated HER2 (p-HER2) levels. In studies of trastuzumab-resistant SKBR3R and BT474R cells, we found that the association between MUC1-C and HER2 is markedly increased (~20-fold) as compared to that in sensitive cells. Additionally, silencing MUC1-C in the trastuzumab-resistant cells or treatment with GO-203 decreased p-HER2 and AKT activation. Moreover, targeting MUC1-C was associated with downregulation of phospho-p27 and cyclin E, which confer trastuzumab resistance. Consistent with these results, targeting MUC1-C inhibited the growth and clonogenic survival of both trastuzumab-resistant cells. Our results further demonstrate that silencing MUC1-C reverses resistance to trastuzumab and that the combination of GO-203 and trastuzumab is highly synergistic. These findings indicate that MUC1-C contributes to constitutive activation of the HER2 pathway and that targeting MUC1-C represents a potential approach to abrogate trastuzumab resistance.en-USMUC1HER2HER3trastuzumabresistancebreast cancerJournal Article2015-01-0510.1038/onc.2013.308