雌激素受体β和p53的体细胞缺失协同作用诱导乳腺肿瘤发生。
Somatic loss of estrogen receptor beta and p53 synergize to induce breast tumorigenesis.
作者信息
Bado Igor, Nikolos Fotis, Rajapaksa Gayani, Wu Wanfu, Castaneda Jessica, Krishnamurthy Savitri, Webb Paul, Gustafsson Jan-Åke, Thomas Christoforos
机构信息
Department of Biology and Biochemistry, Center for Nuclear Receptors and Cell Signaling, University of Houston, 3517 Cullen Blvd, Houston, TX, 77204, USA.
Department of Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA.
出版信息
Breast Cancer Res. 2017 Jul 3;19(1):79. doi: 10.1186/s13058-017-0872-z.
BACKGROUND
Upregulation of estrogen receptor beta (ERβ) in breast cancer cells is associated with epithelial maintenance, decreased proliferation and invasion, and a reduction in the expression of the receptor has been observed in invasive breast tumors. However, proof of an association between loss of ERβ and breast carcinogenesis is still missing.
METHODS
To study the role of ERβ in breast oncogenesis, we generated mouse conditional mutants with specific inactivation of ERβ and p53 in the mammary gland epithelium. For epithelium-specific knockout of ERβ and p53, ERβ and p53 mice were crossed to transgenic mice that express the Cre recombinase under the control of the human keratin 14 promoter.
RESULTS
Somatic loss of ERβ significantly accelerated formation of p53-deficient mammary tumors. Loss of the receptor also resulted in the development of less differentiated carcinomas with stronger spindle cell morphology and decreased expression of luminal epithelial markers.
CONCLUSIONS
Our results show that synergism between ERβ and p53 inactivation functions to determine important aspects of breast oncogenesis and cancer progression.
背景
乳腺癌细胞中雌激素受体β（ERβ）的上调与上皮维持、增殖和侵袭减少相关，且在浸润性乳腺肿瘤中已观察到该受体表达降低。然而，ERβ缺失与乳腺癌发生之间关联的证据仍然缺乏。
方法
为研究ERβ在乳腺肿瘤发生中的作用，我们构建了乳腺上皮中ERβ和p53特异性失活的小鼠条件性突变体。为实现ERβ和p53的上皮特异性敲除，将ERβ和p53小鼠与在人角蛋白14启动子控制下表达Cre重组酶的转基因小鼠杂交。
结果
ERβ的体细胞缺失显著加速了p53缺陷型乳腺肿瘤的形成。该受体的缺失还导致了分化程度较低的癌的发生，具有更强的梭形细胞形态且管腔上皮标志物表达降低。
结论
我们的结果表明，ERβ和p53失活之间的协同作用决定了乳腺肿瘤发生和癌症进展的重要方面。
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