PDF(Pubmed)
Abstract：
Pregnancy-associated breast cancer (PABC) is diagnosed during or shortly after pregnancy. Although rare, PABC is a serious occurrence often of the triple negative (TNBC) subtype. Here we show progesterone, prolactin, and RANKL upregulate BRCA1-IRIS (IRIS) in separate and overlapping subpopulations of human mammary epithelial cell lines, which exacerbates the proliferation, survival, and the TNBC-like phenotype in them. Conversely, vitamin D3 reduces IRIS expression in TNBC cell lines, which attenuates growth, survival, and the TNBC-like phenotype in them. In the mouse, Brca1-Iris (Iris, mouse IRIS homolog) is expressed at low-level in nulliparous mice, increases ~10-fold in pregnant/lactating mice, to completely disappear in involuting mice, and reappears at low-level in regressed glands. Mice underwent 3 constitutive pregnancies followed by a forced involution (after 5 days of lactation) contained ~10-fold higher Iris in their mammary glands compared to those underwent physiological involution (after 21 days of lactation). While protein extracts from lactating glands promote proliferation in IRISlow and IRIS overexpressing (IRISOE) cells, extracts from involuting glands promote apoptosis in IRISlow, and aneuploidy in IRISOE cells. In a cohort of breast cancer patients, lack of breastfeeding was associated with formation of chemotherapy resistant, metastatic IRISOE breast cancers. We propose that terminal differentiation triggered by long-term breastfeeding reduces IRIS expression in mammary cells allowing their elimination by the inflammatory microenvironment during physiological involution. No/short-term breastfeeding retains in the mammary gland IRISOE cells that thrive in the inflammatory microenvironment during forced involution to become precursors for aggressive breast cancers shortly after pregnancy.
摘要：
妊娠相关乳腺癌（PABC）在怀孕期间或怀孕后不久被诊断出来。虽然罕见，PABC是一种严重的经常发生的三阴性（TNBC）亚型。这里我们展示黄体酮,催乳素,和RANKL上调BRCA1-IRIS（IRIS）在人乳腺上皮细胞系的分离和重叠亚群，这加剧了扩散，生存,以及它们的TNBC样表型。相反，维生素D3降低TNBC细胞系中的IRIS表达，这会削弱生长，生存,以及它们的TNBC样表型。在老鼠身上，Brca1-Iris(Iris,小鼠IRIS同源物）在未产小鼠中低水平表达，在怀孕/哺乳期小鼠中增加〜10倍，在渐消的老鼠中完全消失，并在退化的腺体中以低水平重新出现。小鼠经历了3次组成型妊娠，然后进行了强制退化（泌乳5天后），其乳腺中的虹膜比生理退化（泌乳21天后）高出约10倍。虽然来自泌乳腺的蛋白质提取物促进IRISlow和IRIS过表达（IRISOE）细胞的增殖，从渐退腺体中提取的提取物促进IRISlow细胞凋亡，和IRISOE细胞的非整倍性。在一群乳腺癌患者中，缺乏母乳喂养与化疗耐药的形成有关，转移性IRISOE乳腺癌。我们建议，长期母乳喂养引发的终末分化会降低乳腺细胞中IRIS的表达，从而使其在生理退化过程中被炎症微环境消除。无/短期母乳喂养保留在乳腺IRISOE细胞中，这些细胞在被迫复旧期间在炎症微环境中茁壮成长，成为妊娠后不久侵袭性乳腺癌的前体。
