PTHrP induces STAT5 activation, secretory differentiation and accelerates mammary tumor development.
PTHrP induces STAT5 activation, secretory differentiation and accelerates mammary tumor development.
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DOI：
10.1186/s13058-022-01523-1
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发表时间：
2022-04-19
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甲状旁腺素相关蛋白（PTHrP）是胚胎乳房发育所必需的，并且在哺乳期间具有重要功能，当其由肺泡上皮细胞产生并分泌到母体循环中以动员用于产奶的骨骼钙时。PTHrP也由乳腺癌产生，GWAS研究表明它会影响乳腺癌的风险。然而，PTHrP在乳腺癌生物学中的确切功能仍不清楚。我们开发了一种四环素调节的MMTV（小鼠乳腺肿瘤病毒）驱动的乳腺上皮细胞PTHrP过表达模型（Tet-PTHrP小鼠），并将这些小鼠与MMTV-PyMT（多瘤中瘤抗原）乳腺癌模型进行繁殖，以分析PTHrP过表达对正常乳腺生物学和乳腺癌进展的影响。PTHrP在腔上皮细胞中的过表达引起乳腺上皮的肺泡增生和分泌分化，并伴随乳汁分泌。这伴随着Stat 5的激活和E74样因子-5（Elf 5）的表达增加以及泌乳后退化的延迟。在MMTV-PyMT小鼠中，PTHrP（Tet-PTHrP;PyMT小鼠）的过表达缩短了肿瘤潜伏期并加速了肿瘤生长，最终降低了总生存期。肿瘤过度生产PTHrP也表现出核pSTAT 5和Elf 5的表达增加，分泌分化和乳汁成分的标志物的表达增加，组织学上类似于乳腺分泌性癌。从肿瘤分离的细胞内PTHrP的过表达，而不是PTHrP外源添加到细胞培养基中，导致STAT 5和乳蛋白基因表达的激活。此外，无论是消融上皮细胞中的1型PTH/PTHrP受体（PTH 1 R），还是用抗PTH 1 R抗体治疗Tet-PTHrP;PyMT小鼠，都不能阻止分泌分化或改变肿瘤潜伏期。这些数据表明，PTHrP的行为在细胞自主，内分泌的方式。最后，PTHrP在人乳腺癌中的表达与参与乳汁产生和STAT 5信号传导的基因的表达相关。我们的研究表明，PTHrP促进途径导致分泌分化和增殖在正常乳腺上皮细胞和乳腺肿瘤细胞。在线版本包含补充材料，可通过10.1186/s13058-022-01523-1获得。
Parathyroid hormone-related protein (PTHrP) is required for embryonic breast development and has important functions during lactation, when it is produced by alveolar epithelial cells and secreted into the maternal circulation to mobilize skeletal calcium used for milk production. PTHrP is also produced by breast cancers, and GWAS studies suggest that it influences breast cancer risk. However, the exact functions of PTHrP in breast cancer biology remain unsettled. We developed a tetracycline-regulated, MMTV (mouse mammary tumor virus)-driven model of PTHrP overexpression in mammary epithelial cells (Tet-PTHrP mice) and bred these mice with the MMTV-PyMT (polyoma middle tumor-antigen) breast cancer model to analyze the impact of PTHrP overexpression on normal mammary gland biology and in breast cancer progression. Overexpression of PTHrP in luminal epithelial cells caused alveolar hyperplasia and secretory differentiation of the mammary epithelium with milk production. This was accompanied by activation of Stat5 and increased expression of E74-like factor-5 (Elf5) as well as a delay in post-lactation involution. In MMTV-PyMT mice, overexpression of PTHrP (Tet-PTHrP;PyMT mice) shortened tumor latency and accelerated tumor growth, ultimately reducing overall survival. Tumors overproducing PTHrP also displayed increased expression of nuclear pSTAT5 and Elf5, increased expression of markers of secretory differentiation and milk constituents, and histologically resembled secretory carcinomas of the breast. Overexpression of PTHrP within cells isolated from tumors, but not PTHrP exogenously added to cell culture media, led to activation of STAT5 and milk protein gene expression. In addition, neither ablating the Type 1 PTH/PTHrP receptor (PTH1R) in epithelial cells nor treating Tet-PTHrP;PyMT mice with an anti-PTH1R antibody prevented secretory differentiation or altered tumor latency. These data suggest that PTHrP acts in a cell-autonomous, intracrine manner. Finally, expression of PTHrP in human breast cancers is associated with expression of genes involved in milk production and STAT5 signaling. Our study suggests that PTHrP promotes pathways leading to secretory differentiation and proliferation in both normal mammary epithelial cells and in breast tumor cells. The online version contains supplementary material available at 10.1186/s13058-022-01523-1.
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影响因子：
4.8
作者：
Gunther, EJ;Belka, GK;Chodosh, LA
通讯作者：
Chodosh, LA
影响因子：
4.4
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影响因子：
5.3
作者：
GUY, CT;CARDIFF, RD;MULLER, WJ
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MULLER, WJ