Fibronectin rescues estrogen receptor α from lysosomal degradation in breast cancer cells

• DOI: 10.1083/jcb.201703037
• Publication Date: 2018-07-06T14:08:26Z
• Authors: Rocío G. Sampayo; Andrés M. Toscani; Matthew G. Rubashkin; Kate Thi; Luciano A. Masullo; Ianina L. Violi; Jonathon N. Lakins; Alfredo Cáceres; William C. Hines; Federico Coluccio...; Fernando D. Stefani; Dante R. Chialvo; Mina J. Bissell; Valerie M. Weaver; Marina Simian
• Keywords: 0301 basic medicine; 1.1 Normal biological development and functioning; receptor; Endosomes; Medical and Health Sciences; Models, Biological; Cell Line; 03 medical and health sciences; breast cancer; Underpinning research; Models; fibronectin; Cell Line, Tumor; Breast Cancer; https://purl.org/becyt/ford/3.1; estrogen; Tumor Microenvironment; Humans; https://purl.org/becyt/ford/3; Research Articles; Cancer; Tumor; Integrin beta1; Estrogen Receptor alpha; Biological Sciences; Biological; Estrogen; Extracellular Matrix; Fibronectins; 3. Good health; Protein Transport; Proteolysis; MCF-7 Cells; Lysosomes; Developmental Biology

Estrogen receptor α (ERα) is expressed in tissues as diverse as brains and mammary glands. In breast cancer, ERα is a key regulator of tumor progression. Therefore, understanding what activates ERα is critical for cancer treatment in particular and cell biology in general. Using biochemical approaches and superresolution microscopy, we show that estrogen drives membrane ERα into endosomes in breast cancer cells and that its fate is determined by the presence of fibronectin (FN) in the extracellular matrix; it is trafficked to lysosomes in the absence of FN and avoids the lysosomal compartment in its presence. In this context, FN prolongs ERα half-life and strengthens its transcriptional activity. We show that ERα is associated with β1-integrin at the membrane, and this integrin follows the same endocytosis and subcellular trafficking pathway triggered by estrogen. Moreover, ERα+ vesicles are present within human breast tissues, and colocalization with β1-integrin is detected primarily in tumors. Our work unravels a key, clinically relevant mechanism of microenvironmental regulation of ERα signaling.