Sun Xuan, Glynn Danielle J, Hodson Leigh J, Huo Cecilia, Britt Kara, Thompson Erik W, Woolford Lucy, Evdokiou Andreas, Pollard Jeffrey W, Robertson Sarah A, Ingman Wendy V
Discipline of Obstetrics and Gynaecology, School of Medicine, University of Adelaide, Adelaide, Australia.
The Robinson Research Institute, University of Adelaide, Adelaide, Australia.
Breast Cancer Res. 2017 Jan 11;19(1):4. doi: 10.1186/s13058-016-0796-z.
Macrophages play diverse roles in mammary gland development and breast cancer. CC-chemokine ligand 2 (CCL2) is an inflammatory cytokine that recruits macrophages to sites of injury. Although CCL2 has been detected in human and mouse mammary epithelium, its role in regulating mammary gland development and cancer risk has not been explored.
Transgenic mice were generated wherein CCL2 is driven by the mammary epithelial cell-specific mouse mammary tumour virus 206 (MMTV) promoter. Estrous cycles were tracked in adult transgenic and non-transgenic FVB mice, and mammary glands collected at the four different stages of the cycle. Dissected mammary glands were assessed for cyclical morphological changes, proliferation and apoptosis of epithelium, macrophage abundance and collagen deposition, and mRNA encoding matrix remodelling enzymes. Another cohort of control and transgenic mice received carcinogen 7,12-Dimethylbenz(a)anthracene (DMBA) and tumour development was monitored weekly. CCL2 protein was also quantified in paired samples of human breast tissue with high and low mammographic density.
Overexpression of CCL2 in the mammary epithelium resulted in an increased number of macrophages, increased density of stroma and collagen and elevated mRNA encoding matrix remodelling enzymes lysyl oxidase (LOX) and tissue inhibitor of matrix metalloproteinases (TIMP)3 compared to non-transgenic controls. Transgenic mice also exhibited increased susceptibility to development of DMBA-induced mammary tumours. In a paired sample cohort of human breast tissue, abundance of epithelial-cell-associated CCL2 was higher in breast tissue of high mammographic density compared to tissue of low mammographic density.
Constitutive expression of CCL2 by the mouse mammary epithelium induces a state of low level chronic inflammation that increases stromal density and elevates cancer risk. We propose that CCL2-driven inflammation contributes to the increased risk of breast cancer observed in women with high mammographic density.
巨噬细胞在乳腺发育和乳腺癌中发挥着多种作用。CC趋化因子配体2（CCL2）是一种炎症细胞因子，可将巨噬细胞募集到损伤部位。尽管在人和小鼠乳腺上皮中已检测到CCL2，但其在调节乳腺发育和癌症风险中的作用尚未得到探索。
构建转基因小鼠，其中CCL2由乳腺上皮细胞特异性小鼠乳腺肿瘤病毒206（MMTV）启动子驱动。在成年转基因和非转基因FVB小鼠中追踪发情周期，并在周期的四个不同阶段收集乳腺。对解剖后的乳腺进行评估，观察其周期性形态变化、上皮细胞的增殖和凋亡、巨噬细胞丰度和胶原沉积，以及编码基质重塑酶的mRNA。另一组对照和转基因小鼠接受致癌物7,12-二甲基苯并(a)蒽（DMBA），每周监测肿瘤发展情况。还对乳腺X线密度高和低的人乳腺组织配对样本中的CCL2蛋白进行了定量。
与非转基因对照相比，乳腺上皮中CCL2的过表达导致巨噬细胞数量增加、基质和胶原密度增加，以及编码基质重塑酶赖氨酰氧化酶（LOX）和基质金属蛋白酶组织抑制剂（TIMP）3的mRNA水平升高。转基因小鼠对DMBA诱导的乳腺肿瘤发生也表现出更高的易感性。在人乳腺组织配对样本队列中，乳腺X线密度高的乳腺组织中上皮细胞相关CCL2的丰度高于乳腺X线密度低的组织。
小鼠乳腺上皮细胞组成性表达CCL2会诱导一种低水平慢性炎症状态，增加基质密度并提高癌症风险。我们认为，CCL2驱动的炎症导致乳腺X线密度高的女性患乳腺癌风险增加。
