The HER3/4
ligand heregulin-β2 (
HRG) is a secreted
growth factor that transactivates the
ligand-less receptor HER2 to promote aggressive phenotypes in
breast cancer.
HRG can also localize to the nucleus of
breast cancer cells, but both the nuclear translocation mechanism and the physiological role of nuclear
HRG remain elusive. Here we show that
nucleolin-driven nuclear moonlighting of
HRG uncouples its role as a driver of endocrine resistance from its canonical HER network-activating role in
breast cancer. Tandem affinity purification coupled to mass spectrometry identified the intracellular transporter
nucleolin as a major
HRG-
binding protein.
HRG interacts with
nucleolin via a
nuclear localization signal motif located at the N-terminal extracellular domain of
HRG.
Nucleolin interacts with
HRG via
aspartate/
glutamate-rich acidic stretches located at the N-terminal domain of
nucleolin. Depletion of
nucleolin abolishes
HRG nuclear translocation and decreases
HRG mRNA and
protein expression. Isolated deficiency of nuclear
HRG abolishes the
HRG-driven endocrine resistance phenotype in vitro and in mouse xenograft models, while preserving its capacity to activate the
HRG/HER/MAPK autocrine signaling axis. Conversely, isolated deficiency of secreted
HRG to bind HER2/3 receptors does not impair endocrine resistance. The discovery that the functions of dual compartment-resident
HRG do not depend on the same effector (i.e., activation of HER2/3 receptors) establishes a new paradigm for the functional and therapeutic relevance of nuclear
HRG in
breast cancer.