Recent studies have shown that stress can substantially facilitate breast cancer metastasis,which can be reduced by nonselective β1/β2-adrenergic receptor(β1/β2-AR)blocker.However,several side effects were identified.Thus,it is extremely warranted to explore more effective and better-tolerated β2-AR blocker.Currently,we demonstrated that baicalin(BA),a major bioactive component of Scutellaria bai-calensis Georgi,could significantly attenuate stress hormones especially epinephrine(Epi)-induced breast cancer cell migration and invasion in vitro.Mechanistically,we identified that β2-AR was a direct target of BA via the drug affinity responsive target stability(DARTS)combined with mass spectrum assay,and BA photoaffinity probe with pull-down assay,which was further confirmed by a couple of bio-physical and biochemical assays.Furthermore,we demonstrated that BA could directly bind to the Phe-193 and Phe-289 of β2-AR,subsequently inhibit cyclic adenosine monophosphate-protein kinase A-focal adhesion kinase(cAMP-PKA-FAK)pathway,and thus impede epithelial-mesenchymal transition(EMT),thereby hindering the metastatic progression of the chronic stress coupled with syngeneic and xenograft in vivo orthotopic and tail vein mouse model.These findings firstly identify BA as a potential β2-AR inhibitor in the treatment of stress-induced breast cancer metastasis.

A 19-year-old female patient received risperidone 3 mg twice daily for schizophrenia. She did not have nipple discharge before taking the drug. After taking the drug, nipple discharge occurred intermittently. One year later, a mass with pain in the right breast was found, which could not be alleviated after treatments with Rupi Sanjie capsules (乳癖散结胶囊), cefdinir, ibuprofen, rifampicin, and isoniazid and continued to increase, accompanied by bilateral knee pain, nodular erythema and tenderness of lower limbs. Laboratory tests showed white blood cell count 18.4×10 9/L and serum prolactin 37.42 μg/L. Ultrasonography of the right breast showed a 13.2 cm×11.0 cm×3.0 cm area low echo with unclear boundary, local fluidity, and abundant blood flow signals around. Granulomatous lobular mastitis of right breast (abscess stage) and hyperprolactiemia was diagnosed. After excluding physiological and pathological reasons, it was considered that risperidone caused hyperprolactinemia, which then induced granulomatous mastitis. However, risperidone could not be stopped without the guidance of a specialist, so only abscess incision, drainage, debridement, anti-infection, and anti-inflammatory were given. Purulent secretions gradually decreased, pain alleviated, and erythema of lower limbs partially subsided. Then risperidone dose was adjusted to 2 mg twice daily under the guidance of her psychiatrist. The serum prolactin level decreased (28.36 μg/L). At 1 year of follow-up, granulomatous mastitis did not recur.

A 19-year-old female patient received risperidone 3 mg twice daily for schizophrenia. She did not have nipple discharge before taking the drug. After taking the drug, nipple discharge occurred intermittently. One year later, a mass with pain in the right breast was found, which could not be alleviated after treatments with Rupi Sanjie capsules (乳癖散结胶囊), cefdinir, ibuprofen, rifampicin, and isoniazid and continued to increase, accompanied by bilateral knee pain, nodular erythema and tenderness of lower limbs. Laboratory tests showed white blood cell count 18.4×10 9/L and serum prolactin 37.42 μg/L. Ultrasonography of the right breast showed a 13.2 cm×11.0 cm×3.0 cm area low echo with unclear boundary, local fluidity, and abundant blood flow signals around. Granulomatous lobular mastitis of right breast (abscess stage) and hyperprolactiemia was diagnosed. After excluding physiological and pathological reasons, it was considered that risperidone caused hyperprolactinemia, which then induced granulomatous mastitis. However, risperidone could not be stopped without the guidance of a specialist, so only abscess incision, drainage, debridement, anti-infection, and anti-inflammatory were given. Purulent secretions gradually decreased, pain alleviated, and erythema of lower limbs partially subsided. Then risperidone dose was adjusted to 2 mg twice daily under the guidance of her psychiatrist. The serum prolactin level decreased (28.36 μg/L). At 1 year of follow-up, granulomatous mastitis did not recur.