Loss of amphiregulin reduces myoepithelial cell coverage of mammary ducts and alters breast tumor growth.
Loss of amphiregulin reduces myoepithelial cell coverage of mammary ducts and alters breast tumor growth.
复制标题
DOI：
10.1186/s13058-018-1057-0
复制
发表时间：
2018-10-26
期刊：
影响因子：
--
通讯作者：
Segall JE
中科院分区：
文献类型：
--
作者：
Mao SPH;Park M;Cabrera RM;Christin JR;Karagiannis GS;Oktay MH;Zaiss DMW;Abrams SI;Guo W;Condeelis JS;Kenny PA;Segall JE
双调蛋白（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。在没有AREG的情况下，乳腺导管生长发育迟缓，不能扩张。此外，雌激素受体阳性乳腺肿瘤细胞中AREG表达的抑制抑制了体外和体内生长。我们将AREG-null（AREG-/-）小鼠与小鼠管腔型B乳腺癌模型MMTV-PyMT（PyMT）杂交，以产生缺乏AREG的自发性乳腺肿瘤（AREG-/-PyMT）。我们评估了肿瘤生长、细胞角蛋白-8（K8）阳性管腔细胞、细胞角蛋白-14（K14）阳性肌上皮细胞以及AREG、Ki 67和PyMT的表达。对来自非荷瘤AREG+/+小鼠的原代肌上皮细胞进行荧光激活细胞分选，并使其适应培养，用于与AT-3细胞（一种源自C57 B1/6 PyMT乳腺肿瘤的细胞系）的体外共培养研究。有趣的是，PyMT诱导的病变在AREG−/−小鼠中比在AREG+/+小鼠中进展得更快。非PyMT AREG−/−乳腺中K8+管腔和K14+肌上皮细胞的定量显示K14+细胞较少，肌上皮层较薄。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以抑制PyMT表达。晚期AREG−/− PyMT肿瘤的结构明显不那么坚固，有更多的乳头状和囊性生长区域。乳头状区域的增生和坏死均较少。在癌症基因组图谱数据库中，管腔-B浸润性乳头状癌的AREG表达低于管腔B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表达中以前未知的作用。AREG表达对于乳腺导管的适当肌上皮覆盖是必不可少的。AREG和肌上皮细胞均可抑制PyMT的表达。我们发现，在MMTV-PyMT模型和人乳腺癌中，AREG表达降低与浸润性乳头状乳腺癌相关。本文的在线版本（10.1186/s13058-018-1057-0）包含补充材料，可供授权用户使用。
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. The online version of this article (10.1186/s13058-018-1057-0) contains supplementary material, which is available to authorized users.