HOXA9 regulates BRCA1 expression to modulate human breast tumor phenotype
HOXA9 regulates BRCA1 expression to modulate human breast tumor phenotype
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DOI：
10.1172/jci39534
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发表时间：
2010-05-01
影响因子：
15.9
通讯作者：
Weaver, Valerie M.
中科院分区：
文献类型：
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作者：
Gilbert, Penney M.;Mouw, Janna K.;Weaver, Valerie M.
乳腺癌1，早发性（BRCA 1）表达在散发性乳腺肿瘤中经常减少，即使在没有BRCA 1基因修饰的情况下，但其分子基础尚不清楚。在这项研究中，我们确定了同源框A9（HOXA 9）作为一个基因经常下调人类乳腺癌和肿瘤细胞系，并指出，减少HOXA 9转录水平与肿瘤的侵略，转移和患者死亡率。实验表明，HOXA 9的缺失促进了乳腺上皮细胞的生长和存活，并扰乱了组织形态发生。恢复HOXA 9表达抑制生长和存活，并抑制培养物和异种移植小鼠模型中乳腺癌细胞的恶性表型。分子研究表明HOXA 9通过直接调节BRCA 1的表达来限制乳腺肿瘤的行为。事实上，野生型BRCA 1的异位表达表型模仿了HOXA 9的肿瘤抑制功能，降低BRCA 1水平或功能抑制了HOXA 9的抗肿瘤活性。同样，HOXA 9表达与临床标本中的BRCA 1相关，并且与乳腺组织中缺乏雌激素受体/孕激素受体表达的患者的肿瘤侵袭性相关。这些发现表明HOXA 9通过调节肿瘤抑制基因BRCA 1的表达来限制乳腺肿瘤的侵袭性，我们认为这为在没有BRCA 1基因修饰的情况下散发性乳腺肿瘤中BRCA 1表达的缺失提供了解释。
Breast cancer 1, early onset (BRCA1) expression is often reduced in sporadic breast tumors, even in the absence of BRCA1 genetic modifications, but the molecular basis for this is unknown. In this study, we identified homeobox A9 (HOXA9) as a gene frequently downregulated in human breast cancers and tumor cell lines and noted that reduced HOXA9 transcript levels associated with tumor aggression, metastasis, and patient mortality. Experiments revealed that loss of HOXA9 promoted mammary epithelial cell growth and survival and perturbed tissue morphogenesis. Restoring HOXA9 expression repressed growth and survival and inhibited the malignant phenotype of breast cancer cells in culture and in a xenograft mouse model. Molecular studies showed that HOXA9 restricted breast tumor behavior by directly modulating the expression of BRCA1. Indeed, ectopic expression of wild-type BRCA1 phenocopied the tumor suppressor function of HOXA9, and reducing BRCA1 levels or function inhibited the antitumor activity of HOXA9. Consistently, HOXA9 expression correlated with BRCA1 in clinical specimens and with tumor aggression in patients lacking estrogen receptor/progesterone receptor expression in their breast tissue. These findings indicate that HOXA9 restricts breast tumor aggression by modulating expression of the tumor suppressor gene BRCA1, which we believe provides an explanation for the loss of BRCA1 expression in sporadic breast tumors in the absence of BRCA1 genetic modifications.