Jin Meihua, Wang Yan, Zhou Tingting, Li Wenzhe, Wen Qingping
Department of Anesthesiology, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
Department of Anesthesiology, Dalian Women and Children's Medical Group, Dalian, China.
J Breast Cancer. 2023 Jun;26(3):268-285. doi: 10.4048/jbc.2023.26.e25.
Invasive ductal carcinoma (IDC) accounts for 90% of triple-negative breast cancer (TNBC). IDC is mainly derived from the breast ductal epithelium which is innervated by the 4th to 6th thoracic sympathetic nerves. However, little is known about the contribution of the interactions between sympathetic nerves and breast cancer cells to the malignant progression of TNBC.
The expression levels of the β-adrenergic receptor (β-AR, encoded by ADRB2 gene), nerve growth factor (NGF), and tropomyosin receptor kinase A (TrkA) were determined using immunohistochemistry (IHC). NGF expression levels in the serum were compared by enzyme-linked immunosorbent assay (ELISA). Cell proliferation was assessed using the Cell Counting Kit-8 assay. The β-AR, NGF, p-ERK, and p-CERB expression levels were determined using western blotting. TNBC cells and neuronal cells of the dorsal root ganglion (DRG) in 2-day-old Sprague Dawley rats were co-cultured. Using norepinephrine (NE), NGF, and β-AR, NGF/TrkA blocker pretreatments, the axon growth of each group of DRG neuron cells was detected by immunofluorescence analysis.
The sympathetic adrenergic neurotransmitter NE activated the ERK signaling pathway in TNBC cells. NE/β-AR signaling promotes NGF secretion. NGF further facilitates the malignant progression of TNBC by increasing sympathetic neurogenesis. In the co-culture assay, the sympathetic adrenergic NE/β-AR signal pathway also enhanced NGF secretion. NGF binds TrkA in DRG neurons and promotes axonal growth.
These results suggest that NE/β-AR pathway promotes cell proliferation and NGF production in triple-negative breast cancer.
浸润性导管癌（IDC）占三阴性乳腺癌（TNBC）的90%。IDC主要起源于由第4至6胸交感神经支配的乳腺导管上皮。然而，关于交感神经与乳腺癌细胞之间的相互作用对TNBC恶性进展的作用知之甚少。
采用免疫组织化学（IHC）检测β-肾上腺素能受体（β-AR，由ADRB2基因编码）、神经生长因子（NGF）和原肌球蛋白受体激酶A（TrkA）的表达水平。通过酶联免疫吸附测定（ELISA）比较血清中NGF表达水平。使用细胞计数试剂盒-8测定法评估细胞增殖。采用蛋白质印迹法测定β-AR、NGF、p-ERK和p-CERB的表达水平。将TNBC细胞与2日龄Sprague Dawley大鼠背根神经节（DRG）的神经元细胞共培养。使用去甲肾上腺素（NE）、NGF以及β-AR、NGF/TrkA阻滞剂预处理，通过免疫荧光分析检测每组DRG神经元细胞的轴突生长。
交感肾上腺素能神经递质NE激活TNBC细胞中的ERK信号通路。NE/β-AR信号促进NGF分泌。NGF通过增加交感神经生成进一步促进TNBC的恶性进展。在共培养试验中，交感肾上腺素能NE/β-AR信号通路也增强了NGF分泌。NGF与DRG神经元中的TrkA结合并促进轴突生长。
这些结果表明，NE/β-AR途径促进三阴性乳腺癌中的细胞增殖和NGF产生。
