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Somatic Mutation of P53 Leads to Estrogen Receptor Alpha-Positive

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Somatic Mutation of P53 Leads to Estrogen Receptor Alpha-Positive [CANCER RESEARCH 64, 3525–3532, May 15, 2004] Somatic Mutation of p53 Leads to Estrogen Receptor ␣-Positive and -Negative Mouse Mammary Tumors with High Frequency of Metastasis Suh-Chin J. Lin,1,2 Kuo-Fen Lee,4 Alexander Yu. Nikitin,5 Susan G. Hilsenbeck,6 Robert D. Cardiff,7 Aihua Li,1,2 Keon-Wook Kang,1,2 Steven A. Frank,3 Wen-Hwa Lee,2 and Eva Y-H. P. Lee1,2 1Departments of Developmental and Cell Biology, 2Biological Chemistry, and 3Ecology and Evolutionary Biology, University of California, Irvine, California; 4The Salk Institute for Biological Studies, La Jolla, California; 5Department of Biomedical Sciences, Cornell University, Ithaca, New York; 6Department of Medicine and Department of Molecular and Cellular Biology, Breast Center, Baylor College of Medicine, Houston, Texas; and 7Center for Comparative Medicine, University of California, Davis, California ABSTRACT tion of p53 in mouse mammary epithelial cells is necessary to generate a mouse model mimicking human carcinogenesis. ␣ Approximately 70% of human breast cancers are estrogen receptor In addition to genetic mutations, steroid hormones play a critical role (ER␣)-positive, but the origins of ER␣-positive and -negative tumors remain in breast carcinogenesis (13). About 70% of human breast cancers are unclear. Hormonal regulation of mammary gland development in mice is ␣ ␣ similar to that in humans; however, most mouse models produce only ER␣- estrogen receptor (ER )-positive and estrogen-dependent (14), and ␣ negative tumors. In addition, these mouse tumors metastasize at a low rate ER and progesterone receptor (PR) expression is an important indicator relative to human breast tumors. We report here that somatic mutations of of potential responses to hormonal therapy (15). However, the factors that p53 in mouse mammary epithelial cells using the Cre/loxP system leads to control ER␣ expression in tumor cells are unknown. Thus far, most ER␣-positive and -negative tumors. p53 inactivation under a constitutive established mouse models seldom produce ER␣-positive mammary tu- active WAPCrec in prepubertal/pubertal mice, but not under MMTVCre in mors (16). In a C3(1)/SV40 T-antigen-transgenic model, ER␣ expression adult mice, leads to the development of ER␣-positive tumors, suggesting that decreases during early mammary tumor progression (from low- to high- target cells or developmental stages can determine ER␣ status in mammary grade mammary intraepithelial neoplasia and becomes undetectable in tumors. Importantly, these tumors have a high rate of metastasis. An inverse invasive tumors (17). In Brca1- and Brca2-linked mammary tumors, the relationship between the number of targeted cells and median tumor latency majority of tumors show no detectable ER␣ expression (18–20). was also observed. Median tumor latency reaches a plateau when targeted cell numbers exceed 20%, implying the existence of saturation kinetics for In humans, breast cancers frequently metastasize to other organs such breast carcinogenesis. Genetic alterations commonly observed in human as liver, lung, and specifically bone (21). Metastasis rather than primary breast cancer including c-myc amplification and Her2/Neu/erbB2 activation tumors are responsible for most cancer mortality (21, 22). Less than 5% were seen in these mouse tumors. Thus, this tumor system reproduces many of patients with metastatic breast cancer have a long-term remission after important features of human breast cancer and provides tools for the study treatment (22). In established mouse mammary tumor models, the tumor of the origins of ER␣-positive and -negative breast tumors in mice. cells infrequently colonize other organs. Only 10% Brca1 tumors (18), 10% ptenϩ/Ϫ tumors (23), and 0% Brca2 tumors (12, 20) metastasize. Many mouse mammary tumor virus (MMTV)/oncogene-bearing trans- INTRODUCTION genic mice have a rare occurrence of metastasis (24), but metastatic Breast carcinogenesis requires multiple genetic changes including in- tumors are observed in polyomavirus middle T antigen and neu proto- activation of tumor suppressor genes and activation of oncogenes (1). oncogene transgenic mice (25, 26). Mutations in p53 are observed in close to half of human cancers including We have generated a mouse breast tumor model by using Cre/loxp breast carcinomas (2). p53 is also mutated in families with Li-Fraumeni method to specifically inactivate p53 in mammary epithelial cells. This ␣ syndrome in which early-onset female breast cancer is the most prevalent conditional inactivation of p53 leads to ER -positive and -negative type of tumor (3). p53 is a transcription factor that regulates genes critical mammary tumors with a high rate of metastasis. We found that p53 for cell cycle arrest and for apoptosis after genotoxic stress, thus prevent- inactivation during specific developmental stages critically determines ␣ ing genome instability (4–6). In addition, amplification and/or overex- ER expression in mammary tumors. This breast tumor system provides pression of c-myc, Her2/Neu/erbB2, and cyclin D1 oncogenes are seen in a close model of the human disease and will be useful for both mecha- ␣ a significant portion of breast cancers (2, 7). nistic and therapeutic studies of ER -positive breast cancer. p53 knockout mice are cancer prone and develop early-onset lym- phoma and sarcoma (8, 9) but rarely mammary tumors (10) because of MATERIALS AND METHODS early mortality. To circumvent this problem, p53null mammary epithe- lium is transplanted into the fat pad of wild-type recipients and leads to Targeting Vector Construction. A 10.75-kb clone covering exons 1–10 of the formation of breast tumors (11). Although this offers a potential p53 was isolated from a 129sv mouse genomic library. The 3.4-kb XhoI- model to study breast tumors, the influence of the transplantation process HindIII fragment containing exons 2–9 was subcloned into pBR322. A re- on carcinogenesis is not clear. Also, the transplanted cells are p53null, placement-type targeting vector was made by inserting the first loxP site into whereas in human tumors somatic mutations are acquired in a subset of a BamHI site located in intron 6. A neo-cassette flanked by two loxP sites was cells during tumor progression. Previously, Jonkers et al. (12) reported inserted into the PvuII site in intron 4. The resulting construct was cleaved with that no mammary tumor formation was observed in p53 conditional- XhoI and HindIII, blunt-ended and subcloned into p2TK (27). The finished targeting construct is designated p53neoloxp32TK. mutant mice carrying K14Cre transgene. Therefore, conditional inactiva- MMTVCre Transgene Construction. The backbone of the MMTVCre transgene is pBSpKCR3 (28) containing part of the rabbit ␤-globin gene (the Received 11/10/03; revised 1/28/04; accepted 3/2/04. end of exon 2, intron 2, and exon 3), and the polyadenylation site. A 1.6-kb Grant support: National Cancer Institute mouse consortium Grant CA04964, DOD BglII-HindIII fragment composed of the Cre transgene with a nuclear local- BC013020, NIH CA84241, Breast Cancer Research Foundation to E. Lee and NCIP30 CA93373 to R. Cardiff. ization signal was inserted within exon 3 of the globin gene of pBSpKCR3.A The costs of publication of this article were defrayed in part by the payment of page 1.5-kb HindIII-NheI fragment containing the MMTV-LTR was cut from pMAM charges. This article must therefore be hereby marked advertisement in accordance with (Clontech, Palo Alto, California) and subcloned 5Ј to exon 2 of the globin 18 U.S.C. Section 1734 solely to indicate this fact. gene. The finished transgene construct is designated pMMTV Cre. Requests for reprints: Eva Y-H. P. Lee, University of California-Irvine, Sprague ␤ Hall, Room 140, 839 Health Science Court, Irvine, CA 92697-4037. Phone: (949) 824- MMTVCre-Transgenic Mice Production. The 4.3-kb XhoI fragment 9766; Fax: (949) 824-9767; E-mail: [email protected]. containing the MMTVCre transgene was excised and purified. The transgenic 3525 ER␣ AND METASTASIS IN p53-MEDIATED BREAST CANCER MODELS founders were generated by microinjecting the MMTVCre transgene fragment of exons 5 and 6 led to an in-frame deletion of 99 codons (codons into the male pronucleus of fertilized eggs derived from CB6F1 ϫ C57BL/6 123–221) that encode part of the DNA-binding domain. The presence intercrosses. Transgenic founders were identified by Southern analysis or PCR of loxP sites in introns 4 and 6 did not interfere with the transcription of tail DNA. The primers for the Cre transgene (363-bp amplified) were CreF of p53, and the full-length p53 protein was detected in p53fp/fp mouse Ј Ј Ј (5 -GGTGTCCAATTTACTGACCGTACA-3 ) and CreR (5 -CGGATCCGC- embryonic fibroblasts in the absence of Cre recombinase (Fig. 1C). A CGCATAACCAGTG-3Ј). All mice were maintained in accordance with the smaller protein product of expected mass of 39 kDa, designated guidelines of Laboratory Animal Research of The University of Texas Health ⌬5,6 fp/fp Science Center at San Antonio and Institutional Animal Care and Use Com- p53 , was detected in p53 mouse embryonic fibroblasts infected mittee of University of California, Irvine. with Cre adenoviruses (Fig. 1C). IR-induced responses demonstrate ⌬5,6 Generation of Conditional p53 Mutant Mice. J1 embryonic stem cells that p53 is transcriptionally inactive and fails to increase p21 ⌬5,6 were electroporated with SalI-linearized p53neoloxp32TK and selected with G418 target gene transcription. In contrast to wild-type p53, mutant p53 and 1-(2-deoxy-2-fluoro-␤-D-arabinofuranosyl)-5-iodouracil. Embryonic stem protein was not stabilized after IR (Fig. 1D). No p53 protein was cells harboring homologous recombination were identified by Southern blotting detected from mouse embryonic fibroblasts derived from p53-null using a 3Ј probe external to the targeting region. The neo-cassette was removed (p53Ϫ/Ϫ) mice (Fig. 1, C and D). from targeted embryonic stem cells by transient expression of pSPCre.Of231 Characterization of Cre-Transgenic Mice. To introduce somatic clones analyzed by Southern blotting, two contained a recombination that removed p53 mutation in the mammary gland, different lines of mice express- only neo.
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