TY - JOUR AB - <jats:title>Abstract</jats:title><jats:p>Approximately 30% of women diagnosed with ERα breast cancer relapse with metastatic disease following adjuvant treatment with endocrine therapies<jats:sup>1,2</jats:sup>. The connection between acquisition of drug resistance and invasive potential is poorly understood. In this study, we demonstrate that the type II keratin topological associating domain (TAD)<jats:sup>3</jats:sup> undergoes epigenetic reprogramming in cells that develop resistance to aromatase inhibitors (AI), leading to keratin 80 (KRT80) upregulation. In agreement, an increased number of KRT80-positive cells are observed at relapse <jats:italic>in vivo</jats:italic> while KRT80 expression associates with poor outcome using several clinical endpoints. KRT80 expression is driven by <jats:italic>de novo</jats:italic> enhancer activation by sterol regulatory element-binding protein 1<jats:sup>4</jats:sup> (SREBP1). KRT80 upregulation directly promotes cytoskeletal rearrangements at the leading edge, increased focal adhesion maturation and cellular stiffening, which collectively promote cancer cell invasion. Shear-wave elasticity imaging of prospective patients shows that KRT80 levels correlate with stiffer tumors <jats:italic>in vivo</jats:italic>. Collectively, our data uncover an unpredicted and potentially targetable direct link between epigenetic and cytoskeletal reprogramming promoting cell invasion in response to chronic AI treatment.</jats:p> AU - Perone,Y AU - Farrugia,AJ AU - Meira,AR AU - Gyrffy,B AU - Ion,C AU - Uggetti,A AU - Patten,D AU - Chronopoulos,A AU - Faronato,M AU - Shousha,S AU - Steel,JH AU - Davies,C AU - Patel,N AU - Rio,Hernandez AD AU - Coombes,C AU - Pruneri,G AU - Lim,A AU - Calvo,F AU - Magnani,L DO - 10.1101/380634 PY - 2018/// TI - SREBP1 drives KRT80-dependent cytoskeletal changes and invasive behavior in endocrine resistant ERα breast cancer UR - http://dx.doi.org/10.1101/380634 ER -