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Ptenfl/fl ;Trp53fl/fl ;Pbsn-iCre+ 基因编辑小鼠自发形成前列腺癌与乳腺癌的模型构建研究The research on construction of the spontaneous prostate tumor and breast cancer model of
Ptenfl/fl ;Trp53fl/fl ;Pbsn-iCre+ transgenic mouse- 中国癌症杂志 2025年35卷第8期 页码：769-775
- 作者机构：
1. 复旦大学附属肿瘤医院肿瘤研究所，复旦大学上海医学院肿瘤学系，上海 200032
2. 内蒙古大学生命科学学院，内蒙古 呼和浩特 010000
- 作者简介：
[ "吴佳辰（ORCID: 0009-0003-6089-2733），硕士研究生在读。" ]
唐爽（ORCID: 0000-0002-3501-7836），博士，青年研究员、博士研究生导师。
- 基金信息：国家自然科学基金(32270767)
DOI：10.19401/j.cnki.1007-3639.2025.08.005
中图分类号： R737.9;R737.25收稿：2025-03-12，
修回：2025-04-13，
纸质出版：2025-08-30
- 稿件说明：
移动端阅览
吴佳辰, 何丽娜, 汤鑫茹, 等.
Ptenfl/fl ;Trp53fl/fl ;Pbsn-iCre+ 基因编辑小鼠自发形成前列腺癌与乳腺癌的模型构建研究[J]. 中国癌症杂志, 2025,35(8):769-775.Jiachen WU, Lina HE, Xinru TANG, et al. The research on construction of the spontaneous prostate tumor and breast cancer model of
Ptenfl/fl ;Trp53fl/fl ;Pbsn-iCre+ transgenic mouse[J]. China Oncology, 2025, 35(8): 769-775.吴佳辰, 何丽娜, 汤鑫茹, 等.
Ptenfl/fl ;Trp53fl/fl ;Pbsn-iCre+ 基因编辑小鼠自发形成前列腺癌与乳腺癌的模型构建研究[J]. 中国癌症杂志, 2025,35(8):769-775. DOI： 10.19401/j.cnki.1007-3639.2025.08.005.Jiachen WU, Lina HE, Xinru TANG, et al. The research on construction of the spontaneous prostate tumor and breast cancer model of
Ptenfl/fl ;Trp53fl/fl ;Pbsn-iCre+ transgenic mouse[J]. China Oncology, 2025, 35(8): 769-775. DOI： 10.19401/j.cnki.1007-3639.2025.08.005.
摘要
背景与目的：
前列腺癌与乳腺癌作为高发恶性肿瘤，其发生、发展与抑癌基因10号染色体上缺失的磷酸酶与张力蛋白同源物基因（phosphatase and tensin homolog deleted on chremosome ten，
Pten
）及转化相关蛋白53基因（transformation related protein 53 gene，
Trp53
）的功能缺失密切相关，二者同时缺失可加速肿瘤恶性进展并诱导治疗抵抗。基于Cre-loxP系统的基因编辑小鼠自发性肿瘤模型是研究癌症机制的关键工具。研究表明，前列腺特异性启动子前泌蛋白（probasin
Pbsn）的基因驱动的iCre重组酶基因（
Pbsn-iCre
）可诱导雄性小鼠自发性前列腺癌，但其在雌性乳腺癌中的作用及跨性别表达特征尚未阐明。本研究构建
Pten
fl/fl
;
Trp53
fl/fl
;
Pbsn-iCre
+
转基因小鼠模型，旨在探究其在前列腺癌与乳腺癌中的自发性肿瘤表型，并验证
Pbsn
在乳腺组织中的表达特征。
方法：
利用Cre-loxP系统，通过杂交及连续回交筛选获得基因型稳定的
Pten
fl/fl
;
Trp53
fl/fl
;
Pbsn-iCre
+
子代小鼠（伦理审查批号：FUSCC-IACUC-2025115）。通过聚合酶链式反应及琼脂糖凝胶电泳验证
Pten
、
Trp53
及
Pbsn-iCre
基因型。通过H-E染色评估肿瘤组织病理学特征。免疫组织化学分析前列腺及乳腺肿瘤组织中Pten、p53蛋白表达水平，并检测Pbsn在乳腺、前列腺、卵巢、心脏、肝脏及肾脏中的分布。
结果：
Pten
fl/fl
;
Trp53
fl/fl
;
Pbsn-iCre
+
雄鼠与雌鼠分别自发前列腺癌或乳腺癌。前列腺癌病理学特征表现为肿瘤呈侵袭性腺泡腺癌结构，伴腺体结构紊乱及基膜破坏；乳腺癌病理学特征表现为浸润性导管癌，伴导管上皮异型增生及间质淋巴细胞浸润。免疫组织化学检测证实前列腺及乳腺的肿瘤组织中Pten与p53蛋白完全失表达，验证了前列腺和乳腺特异性基因敲除效应。免疫组织化学检测也证实了Pbsn蛋白特异性表达于前列腺腺泡上皮、卵泡及乳腺导管上皮细胞，而心脏、肝脏及肾脏中未见表达。
结论：
Pbsn-iCre
在雌性乳腺中存在功能性表达，
Pbsn-iCre
所诱导的
Pten
/
Trp53
同时缺失可驱动雄鼠自发形成前列腺癌、雌鼠自发形成乳腺癌。
Abstract
Background and purpose:
Prostate cancer and breast cancer are highly prevalent malignant tumors
and there occurrence and development are related to the tumor suppressor genes phosphatase and tensin homolog de
leted on chremosome ten (
Pten
) and the transformation related protein 53 gene (
Trp53
). The loss of function of
Trp53
is closely related. The simultaneous loss of the two can accelerate the malignant progression of tumors and induce therapeutic resistance. The gene-edited spontaneous tumor model of mice based on the Cre-loxP system is a key tool for studying the mechanism of cancer. Studies have shown that prostate-specific promoter (probasin
Pbsn)-driven iCre recombinase (
Pbsn-iCre
) can induce spontaneous prostate cancer in male mice
but its role in female breast cancer and transgender expression characteristics have not yet been clarified. In this study
we constructed
Pten
fl/fl
;
Trp53
fl/fl
;
Pbsn-iCre
+
transgenic mouse model which was designed to explore its spontaneous tumor phenotype in prostate cancer and breast cancer
and to verify the expression characteristics of Pbsn in breast tissue.
Methods:
The
Pten
fl/fl
;
Trp53
fl/fl
;
Pbsn-iCre
+
mouse model was established using Cre-loxP system by hybridization and continuous backcross screening with
Pten
fl/fl
mouse
Trp53
fl/fl
mouse
and
Pbsn-iCre
+
mouse (Ethical No.: FUSCC-IACUC-2025115).
Pten
Trp53
and
Pbsn-iCre
genotypes were verified by polymerase chain reaction and agarose gel electrophoresis. The incidence of tumor in transgenic mice was monitored
and the histopathological characteristics of tumor were evaluated by hematoxylin-eosin staining. The protein levels of Pten and p53 in prostate and breast tumor tissues were analyzed by immunohistochemistry
and the distributions of Pbsn in breast
prostate
ovary
heart
liver and kidney were detected.
Results:
Pten
fl/ fl
;
Trp53
fl/fl
;
Pbsn-iCre
+
male mouse developed spontaneous prostate tumor at age of 5 month
and female mouse developed spontaneous breast tumor at age of 6 months. The pathological manifestations of prostate cancer were invasive acinar adenocarcinoma structure with glandular structure disorder and basement membrane destruction. The pathological manifestations of breast cancer were invasive ductal carcinoma with ductal epithelial dysplasia and interstitial lymphocyte infiltration. Immunohistochemistry confirmed the complete deletion of Pten and p53 proteins in prostate and breast tumor tissues
which verified the prostate and mammary gland specific gene knockout effect. Immunohistochemistry also confirmed that Pbsn protein was specifically expressed in prostate acinar epithelial cells
ovarian tissue
and mammary duct epithelial cells
but not in heart
liver and kidney.
Conclusion:
Pbsn-iCre
is functionally expressed in female mammary glands
and the simultaneous loss of
Pten
/
Trp53
induced by
Pbsn-iCre
may drive the development of prostate cancer in male and breast cancer in female mouse.
关键词
Keywords
references
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