The majority of breast cancer patients who achieve an initial therapeutic response to the human epidermal growth factor receptor 2 (HER-2)-targeted antibody trastuzumab will show disease progression within 1 year. We previously reported the characterization of SKBR3-derived trastuzumabresistant pools. In the current study, we show that HER-2 interacts with insulin-like growth factor

Stress is an out of the norm state caused by emotional or physical insults. While chronic stress is considered harmful, acute stress is thought to cause transient and reversible changes essential for fight or flight. Stress has been anecdotally associated with hair greying, but scientific evidence linking the two is scant. Here, using mouse stress models, we found that acute stress leads to hair greying through rapid depletion of melanocyte stem cells (MeSCs). Combining adrenalectomy, denervation, chemogenetics, cell ablation, and MeSC-specific adrenergic receptor knockout, we found that stress-induced MeSC loss is independent of the immune attack or adrenal hormones. Instead, hair greying results from activation of the sympathetic nervous system that innervates the MeSC niche. Upon stress, sympathetic nerve activation leads to burst release of the neurotransmitter norepinephrine, which acts directly on MeSCs. Norepinephrine drives quiescent MeSCs to proliferate rapidly, followed by migration and differentiation, leading to their permanent depletion from the niche. Transient suppression of MeSC proliferation with topical application of cell cycle inhibitors rescues stress-induced hair greying. Our studies demonstrate that stress-induced neuronal activity can be an upstream trigger that forces stem cells out of quiescence, and suggest that acute stress stimuli can be more detrimental than anticipated by causing rapid and irreversible loss of somatic stem cells.

Highlights d The hair follicle instructs the formation of the APMsympathetic nerve unit via SHH d APM maintains sympathetic innervation to HFSCs d Sympathetic nerve activates HFSCs via synapse-like contacts and norepinephrine d Cold stimulates not only goosebumps but also hair growth