Chelakkot Vipin Shankar, Thomas Kiara, Romigh Todd, Fong Andrew, Li Lin, Ronen Shira, Chen Shuyang, Funchain Pauline, Ni Ying, Arbesman Joshua
Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
Center for Immunotherapy & Precision Immuno-Oncology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
NPJ Precis Oncol. 2023 Sep 7;7(1):85. doi: 10.1038/s41698-023-00437-1.
MC1R, a G-protein coupled receptor, triggers ultraviolet light-induced melanin synthesis and DNA repair in melanocytes and is implicated in the pathogenesis of melanoma. Although widely expressed in different tissue types, its function in non-cutaneous tissue is relatively unknown. Herein, we demonstrate that disruptive MC1R variants associated with melanomagenesis are less frequently found in patients with several cancers. Further exploration revealed that breast cancer tissue shows a significantly higher MC1R expression than normal breast tissue, and knocking down MC1R significantly reduced cell proliferation in vitro and in vivo. Mechanistically, MC1R signaling through the MC1R-cAMP-CREB/ATF-1 and MC1R-ERK-NFκB axes accelerated the G1-S transition in breast cancer cells. Our results revealed a new association between MC1R and breast cancer, which could be potentially targeted therapeutically. Moreover, our results suggest that MC1R-enhancing/activating therapies should be used cautiously, as they might be pro-tumorigenic in certain contexts.
MC1R是一种G蛋白偶联受体，可触发紫外线诱导的黑素细胞中黑色素合成和DNA修复，并与黑色素瘤的发病机制有关。尽管它在不同组织类型中广泛表达，但其在非皮肤组织中的功能相对未知。在此，我们证明与黑色素瘤发生相关的破坏性MC1R变体在几种癌症患者中较少见。进一步研究发现，乳腺癌组织中MC1R表达明显高于正常乳腺组织，敲低MC1R可显著降低体外和体内的细胞增殖。机制上，通过MC1R-cAMP-CREB/ATF-1和MC1R-ERK-NFκB轴的MC1R信号加速了乳腺癌细胞的G1-S期转换。我们的结果揭示了MC1R与乳腺癌之间的新关联，这可能具有潜在的治疗靶点。此外，我们的结果表明，应谨慎使用增强/激活MC1R的疗法，因为它们在某些情况下可能具有促肿瘤作用。
