Loss of function of GATA3 induces basal-like mammary tumors.
Loss of function of GATA3 induces basal-like mammary tumors.
复制标题
GATA3功能丧失可诱导基底样乳腺肿瘤。
作者：
Bai F;Zheng C;Liu X;Chan HL;Liu S;Ma J;Ren S;Zhu WG;Pei XH
目的：GATA3是乳腺管腔上皮细胞分化所必需的转录因子。基底样乳腺癌中GATA3的表达缺失或显著降低。Gata3的功能丧失会损害细胞增殖，这使得研究Gata3缺乏在体内的作用变得困难。我们之前已经证明CDK抑制剂p18INK4c （p18）是GATA3的下游靶点，可以抑制乳腺上皮细胞的增殖和肿瘤发生。GATA3的功能丧失是否以及如何导致基底样乳腺癌仍然是一个谜。方法：在p18基因缺失背景下，制备杂合子种系缺失Gata3的突变小鼠，建立Gata3缺失乳腺肿瘤模型系统，研究Gata3缺失在乳腺肿瘤发生发展过程中调控细胞增殖和异常分化的作用。结果：Gata3单倍体缺失诱导p18抑制乳腺上皮细胞增殖，抑制乳腺腔内分化，促进乳腺基底分化。p18缺失诱导乳腺腔型肿瘤，挽救了Gata3单倍体缺失导致的增殖缺陷。Gata3单倍体缺失加速了p18缺陷乳腺肿瘤的发展，改变了这些肿瘤的性质，导致其恶性和发光向基底转化。在MMTV-PyMT乳腺肿瘤细胞中，Gata3的表达与基础分化标志物呈负相关。管腔肿瘤细胞中Gata3的缺失也通过诱导p18减少细胞增殖，促进基础分化。我们证实GATA3和基础标志物的表达在人类基底样乳腺癌中呈负相关。结论：本研究首次提供了GATA3功能丧失直接诱导基底样乳腺癌的遗传学证据。我们的发现表明基底样乳腺癌也可能起源于腔型癌症。
Purpose: GATA3 is a transcription factor essential for mammary luminal epithelial cell differentiation. Expression of GATA3 is absent or significantly reduced in basal-like breast cancers. Gata3 loss-of-function impairs cell proliferation, making it difficult to investigate the role of GATA3 deficiency in vivo. We previously demonstrated that CDK inhibitor p18INK4c (p18) is a downstream target of GATA3 and restrains mammary epithelial cell proliferation and tumorigenesis. Whether and how loss-of-function of GATA3 results in basal-like breast cancers remains elusive. Methods: We generated mutant mouse strains with heterozygous germline deletion of Gata3 in p18 deficient backgrounds and developed a Gata3 depleted mammary tumor model system to determine the role of Gata3 loss in controlling cell proliferation and aberrant differentiation in mammary tumor development and progression. Results: Haploid loss of Gata3 reduced mammary epithelial cell proliferation with induction of p18, impaired luminal differentiation, and promoted basal differentiation in mammary glands. p18 deficiency induced luminal type mammary tumors and rescued the proliferative defect caused by haploid loss of Gata3. Haploid loss of Gata3 accelerated p18 deficient mammary tumor development and changed the properties of these tumors, resulting in their malignant and luminal-to-basal transformation. Expression of Gata3 negatively correlated with basal differentiation markers in MMTV-PyMT mammary tumor cells. Depletion of Gata3 in luminal tumor cells also reduced cell proliferation with induction of p18 and promoted basal differentiation. We confirmed that expression of GATA3 and basal markers are inversely correlated in human basal-like breast cancers. Conclusions: This study provides the first genetic evidence demonstrating that loss-of-function of GATA3 directly induces basal-like breast cancer. Our finding suggests that basal-like breast cancer may also originate from luminal type cancer.