PT - JOURNAL ARTICLE AU - Siv Gilfillan AU - Shixiong Wang AU - Madhumohan R. Katika AU - Jens Henrik Norum AU - Helga Bergholtz AU - Elisa Fiorito AU - Siri Nordhagen AU - Yogita Sharma AU - Sachin Singh AU - Venkata S. Somisety AU - Anne-Marthe Fosdahl AU - Silje Nord AU - Olav Engebraaten AU - Ole Christian Lingjaerde AU - Anne-Lise Børresen-Dale AU - Kristine Kleivi Sahlberg AU - Therese Sørlie AU - Meritxell Bellet AU - Sandra Lopez-Aviles AU - Antoni Hurtado TI - Breast tumors escape endocrine therapy by ER-independent mechanisms triggered by the coordinated activities of HER2/HER3 and deacetylated FOXA1 AID - 10.1101/2020.09.22.308569 DP - 2020 Jan 01 TA - bioRxiv PG - 2020.09.22.308569 4099 - http://biorxiv.org/content/early/2020/09/23/2020.09.22.308569.short 4100 - http://biorxiv.org/content/early/2020/09/23/2020.09.22.308569.full AB - Hormone-resistance in ER positive breast cancer is associated with high HER2 activity. Yet, the interplay between HER2 and FOXA1 in hormone resistant tumors is not elucidated. Now, we demonstrate that hormone resistant tumors have increased HER2 expression and that FOXA1 mediates the signals of HER2/3 in an Estrogen Receptor independent manner. Our in vitro and in vivo experiments reveal that HER2/HER3 triggers FOXA1 binding at chromatin regions of ER-regulated genes associated with poor prognosis, facilitating their expression and leading to ER-independent growth. Furthermore, our study supports that FOXA1 acetylated by the acetyltransferase EP300 is retained at ER chromatin regions, which enables ER function. By contrast, HER2/3 activation hinders FOXA1 acetylation and facilitates FOXA1 binding at non-ER interacting regions enriched towards poor prognosis genes. Moreover, FOXA1 deacetylation confers insensitivity to anti-ER drugs inhibitory effect in ER positive cells. These results elucidate how post-translational modifications of FOXA1 control transcription independently of ER in hormone-resistant tumors with enhanced HER2/3 signaling.Competing Interest StatementThe authors have declared no competing interest.