Estrogen receptor-positive (ER+) invasive lobular breast cancer (ILC) comprises about ~15% of breast cancer. ILC’s unique genotypic (loss of wild type E-cadherin expression) and phenotypic (small individual round cancer cells that grow in discontinuous nests) are thought to contribute to a distinctive pattern of metastases to serosal membranes. Unlike invasive ductal carcinoma (IDC), ILC metastases often intercalate into the mesothelial layer of the peritoneum and other serosal surfaces. While ER activity is a known driver of ILC proliferation, very little is known about how additional nuclear receptors contribute to ILC’s distinctive biology. In ER+ IDC, we showed previously that glucocorticoid receptor (GR) activity inhibits pro-proliferative gene expression and cell proliferation. Here we examined ER+ ILC models and found that GR activation similarly reduces S-phase entry gene expression and ILC proliferation. While slowing tumor growth rate, our data also suggest that GR activation results in an enhanced metastatic phenotype through increasing integrin-encoding gene expression, extracellular matrix protein adhesion, and mesothelial cell clearance. Moreover, in an intraductal mouse mammary gland model of ILC, we found that GR expression is associated with increased bone metastases despite slowed primary mammary tumor growth. Taken together, our findings suggest GR-mediated gene expression may contribute to the unusual characteristics of ILC biology.
雌激素受体阳性（ER+）浸润性小叶乳腺癌约占乳腺癌的15%。其独特的基因型（野生型E-钙黏蛋白表达缺失）和表型（以不连续巢状生长的小圆形癌细胞）被认为导致其向浆膜转移的特殊模式。与浸润性导管癌不同，浸润性小叶乳腺癌转移灶常嵌入腹膜及其他浆膜表面的间皮层。虽然ER活性是已知的浸润性小叶乳腺癌增殖驱动因素，但其他核受体如何影响其独特生物学特性尚不明确。在ER+浸润性导管癌中，我们先前研究发现糖皮质激素受体（GR）活性可抑制促增殖基因表达和细胞增殖。本研究通过ER+浸润性小叶乳腺癌模型发现，GR激活同样能降低S期进入相关基因表达并抑制肿瘤增殖。值得注意的是，在减缓肿瘤生长速率的同时，数据显示GR激活通过增强整合素编码基因表达、细胞外基质蛋白粘附及间皮细胞清除能力，反而促进了转移表型。此外，在小鼠乳腺导管内浸润性小叶乳腺癌模型中，尽管原发乳腺肿瘤生长减缓，但GR表达与骨转移增加相关。综上，本研究提示GR介导的基因表达可能参与塑造浸润性小叶乳腺癌独特的生物学特征。
肿瘤(癌症)患者之家