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

Estrogen receptor alpha (ER alpha) is expressed in tissues as diverse as brains and mammary glands. In breast cancer, ER alpha is a key regulator of tumor progression. Therefore, understanding what activates ER alpha is critical for cancer treatment in particular and cell biology in general. Using biochemical approaches and superresolution microscopy, we show that estrogen drives membrane ER alpha 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 ER alpha half-life and strengthens its transcriptional activity. We show that ER alpha is associated with beta 1-integrin at the membrane, and this integrin follows the same endocytosis and subcellular trafficking pathway triggered by estrogen. Moreover, ER alpha(+) vesicles are present within human breast tissues, and colocalization with beta 1-integrin is detected primarily in tumors. Our work unravels a key, clinically relevant mechanism of microenvironmental regulation of ERa signaling.