Sizemore G M, Balakrishnan S, Hammer A M, Thies K A, Trimboli A J, Wallace J A, Sizemore S T, Kladney R D, Woelke S A, Yu L, Fernandez S A, Chakravarti A, Leone G, Ostrowski M C
The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.
Department of Cancer Biology & Genetics, The Ohio State University, Columbus, Ohio 43210, USA.
Oncogene. 2017 Apr 20;36(16):2297-2308. doi: 10.1038/onc.2016.383. Epub 2016 Oct 31.
Fibroblasts within the mammary tumor microenvironment are active participants in carcinogenesis mediating both tumor initiation and progression. Our group has previously demonstrated that genetic loss of phosphatase and tensin homolog (PTEN) in mammary fibroblasts induces an oncogenic secretome that remodels the extracellular milieu accelerating ErbB2-driven mammary tumor progression. While these prior studies highlighted a tumor suppressive role for stromal PTEN, how the adjacent normal epithelium transforms in response to PTEN loss was not previously addressed. To identify these early events, we have evaluated both phenotypic and genetic changes within the pre-neoplastic mammary epithelium of mice with and without stromal PTEN expression. We report that fibroblast-specific PTEN deletion greatly restricts mammary ductal elongation and induces aberrant alveolar side-branching. These mice concomitantly exhibit an expansion of the mammary epithelial stem cell (MaSC) enriched basal/myoepithelial population and an increase in in vitro stem cell activity. Further analysis revealed that NOTCH signaling, specifically through NOTCH3, is diminished in these cells. Mechanistically, JAGGED-1, a transmembrane ligand for the NOTCH receptor, is downregulated in the PTEN-null fibroblasts leading to a loss in the paracrine activation of NOTCH signaling from the surrounding stroma. Reintroduction of JAGGED-1 expression within the PTEN-null fibroblasts was sufficient to abrogate the observed increase in colony forming activity implying a direct role for stromal JAGGED-1 in regulation of MaSC properties. Importantly, breast cancer patients whose tumors express both low stromal JAG1 and low stromal PTEN exhibit a shorter time to recurrence than those whose tumors express low levels of either alone suggesting similar stromal signaling in advanced disease. Combined, these results unveil a novel stromal PTEN-to-JAGGED-1 axis in maintaining the MaSC niche, and subsequently inhibiting breast cancer initiation and disease progression.
乳腺肿瘤微环境中的成纤维细胞是致癌过程中的活跃参与者，介导肿瘤的起始和进展。我们小组之前已经证明，乳腺成纤维细胞中磷酸酶和张力蛋白同源物（PTEN）的基因缺失会诱导一种致癌分泌组，重塑细胞外环境，加速ErbB2驱动的乳腺肿瘤进展。虽然这些先前的研究强调了基质PTEN的肿瘤抑制作用，但相邻正常上皮如何响应PTEN缺失而发生转变此前尚未得到解决。为了确定这些早期事件，我们评估了有或无基质PTEN表达的小鼠肿瘤前乳腺上皮内的表型和基因变化。我们报告，成纤维细胞特异性PTEN缺失极大地限制了乳腺导管伸长，并诱导异常的肺泡侧支形成。这些小鼠同时表现出富含乳腺上皮干细胞（MaSC）的基底/肌上皮细胞群的扩张以及体外干细胞活性的增加。进一步分析表明，这些细胞中的NOTCH信号，特别是通过NOTCH3的信号，减弱。从机制上讲，NOTCH受体的跨膜配体JAGGED-1在PTEN缺失的成纤维细胞中下调，导致周围基质对NOTCH信号的旁分泌激活丧失。在PTEN缺失的成纤维细胞中重新引入JAGGED-1表达足以消除观察到的集落形成活性增加，这意味着基质JAGGED-1在调节MaSC特性中起直接作用。重要的是，肿瘤同时表达低水平基质JAG1和低水平基质PTEN的乳腺癌患者比肿瘤仅表达低水平其中一种的患者复发时间更短，这表明在晚期疾病中存在类似的基质信号。综合起来，这些结果揭示了一种新的基质PTEN到JAGGED-1轴，其在维持MaSC生态位，进而抑制乳腺癌起始和疾病进展中发挥作用。
