Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY, 10461, USA.
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
Breast Cancer Res. 2018 Oct 26;20(1):131. doi: 10.1186/s13058-018-1057-0.
Amphiregulin (AREG), a ligand of the epidermal growth factor receptor, is not only essential for proper mammary ductal development, but also associated with breast cancer proliferation and growth. In the absence of AREG, mammary ductal growth is stunted and fails to expand. Furthermore, suppression of AREG expression in estrogen receptor-positive breast tumor cells inhibits in-vitro and in-vivo growth.
We crossed AREG-null (AREG) mice with the murine luminal B breast cancer model, MMTV-PyMT (PyMT), to generate spontaneous breast tumors that lack AREG (AREG PyMT). We evaluated tumor growth, cytokeratin-8 (K8)-positive luminal cells, cytokeratin-14 (K14)-positive myoepithelial cells, and expression of AREG, Ki67, and PyMT. Primary myoepithelial cells from nontumor-bearing AREG mice underwent fluorescence-activated cell sorting and were adapted to culture for in-vitro coculture studies with AT-3 cells, a cell line derived from C57Bl/6 PyMT mammary tumors.
Intriguingly, PyMT-induced lesions progress more rapidly in AREG mice than in AREG mice. Quantification of K8 luminal and K14 myoepithelial cells in non-PyMT AREG mammary glands showed fewer K14 cells and a thinner myoepithelial layer. Study of AT-3 cells indicated that coculture with myoepithelial cells or exposure to AREG, epidermal growth factor, or basic fibroblast growth factor can suppress PyMT expression. Late-stage AREG PyMT tumors are significantly less solid in structure, with more areas of papillary and cystic growth. Papillary areas appear to be both less proliferative and less necrotic. In The Cancer Genome Atlas database, luminal-B invasive papillary carcinomas have lower AREG expression than luminal B invasive ductal carcinomas.
Our study has revealed a previously unknown role of AREG in myoepithelial cell development and PyMT expression. AREG expression is essential for proper myoepithelial coverage of mammary ducts. Both AREG and myoepithelial cells can suppress PyMT expression. We find that lower AREG expression is associated with invasive papillary breast cancer in both the MMTV-PyMT model and human breast cancer.
Amphiregulin（AREG）是表皮生长因子受体的配体，不仅对乳腺导管的正常发育至关重要，而且与乳腺癌的增殖和生长有关。在缺乏 AREG 的情况下，乳腺导管的生长会受到阻碍，无法扩张。此外，抑制雌激素受体阳性乳腺癌细胞中的 AREG 表达会抑制体外和体内生长。
我们将 AREG 基因敲除（AREG）小鼠与 MMTV-PyMT（PyMT）小鼠的乳腺腔 B 型乳腺癌模型杂交，以生成缺乏 AREG 的自发性乳腺肿瘤（AREG PyMT）。我们评估了肿瘤生长、角蛋白-8（K8）阳性腔细胞、角蛋白-14（K14）阳性肌上皮细胞以及 AREG、Ki67 和 PyMT 的表达。来自非肿瘤携带 AREG 小鼠的原发性肌上皮细胞通过荧光激活细胞分选，并适应与 AT-3 细胞共培养的体外培养，AT-3 细胞是源自 C57Bl/6 PyMT 乳腺肿瘤的细胞系。
有趣的是，与 AREG 小鼠相比，PyMT 诱导的病变在 AREG 小鼠中进展更快。在非 PyMT AREG 乳腺中，K8 腔和 K14 肌上皮细胞的定量分析显示 K14 细胞较少，肌上皮层较薄。对 AT-3 细胞的研究表明，与肌上皮细胞共培养或暴露于 AREG、表皮生长因子或碱性成纤维细胞生长因子可抑制 PyMT 的表达。晚期 AREG PyMT 肿瘤的结构明显不那么坚实，具有更多的乳头状和囊性生长区域。乳头状区域似乎增殖较少且坏死较少。在癌症基因组图谱数据库中，腔 B 型浸润性乳头状癌的 AREG 表达低于腔 B 型浸润性导管癌。
我们的研究揭示了 AREG 在肌上皮细胞发育和 PyMT 表达中的一个以前未知的作用。AREG 的表达对于乳腺导管的正常肌上皮覆盖至关重要。AREG 和肌上皮细胞都可以抑制 PyMT 的表达。我们发现，在 MMTV-PyMT 模型和人类乳腺癌中，AREG 表达较低与浸润性乳头状乳腺癌有关。
Zotero 插件
