Selective induction of chemotherapy resistance of mammary tumors in a conditional mouse model for hereditary breast cancer

Rottenberg, Sven; Nygren, Anders O.H.; Pajic, Marina; Leeuwen, Fijs W. B. van; Heijden, Ingrid van der; Wetering, Koen van de; Liu, Xiaoling; Visser, Karin E. de; Gilhuijs, Kenneth G. A.; Tellingen, Olaf van; Schouten, Jan P.; Jonkers, Jos; Borst, Piet

doi:10.1073/pnas.0702955104

Cited by 273 publications

(277 citation statements)

References 47 publications

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“…In some settings efflux pump overexpression may predominate (35), whereas in other settings, blocked apoptosis or senescence may be largely responsible for resistance (18,36). Our studies using RNAi in vivo, together with our observation that relapsed tumors frequently display altered topoisomerase levels compared with the parental tumor, suggest that topoisomerase expression levels are relevant determinants of therapeutic response.…”

Section: Discussionmentioning

confidence: 69%

Topoisomerase levels determine chemotherapy response in vitro and in vivo

Burgess

Doles²,

Zender

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

278

236

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Topoisomerase poisons are chemotherapeutic agents that are used extensively for treating human malignancies. These drugs can be highly effective, yet tumors are frequently refractory to treatment or become resistant upon tumor relapse. Using a pool-based RNAi screening approach and a well characterized mouse model of lymphoma, we explored the genetic basis for heterogeneous responses to topoisomerase poisons in vitro and in vivo. These experiments identified Top2A expression levels as major determinants of response to the topoisomerase 2 poison doxorubicin and showed that suppression of Top2A produces resistance to doxorubicin in vitro and in vivo. Analogously, using a targeted RNAi approach, we demonstrated that suppression of Top1 produces resistance to the topoisomerase 1 poison camptothecin yet hypersensitizes cancer cells to doxorubicin. Importantly, lymphomas relapsing after treatment display spontaneous changes in topoisomerase levels as predicted by in vitro gene knockdown studies. These results highlight the utility of pooled shRNA screens for identifying genetic determinants of chemotherapy response and suggest strategies for improving the effectiveness of topoisomerase poisons in the clinic.A myriad of genetic factors influence the efficacy of cancer chemotherapy, including both somatic changes in the tumor itself as well as genetic polymorphisms present in the patient. These factors include increased expression of detoxification pumps that prevent access of the drug to its target (1), point mutations that disrupt the drug-target interaction (2, 3), and mutations in stress response pathways [e.g., p53 loss (4)]. To tailor treatment successfully to the individual patient, a more complete understanding of the genetic determinants of therapy response is necessary.RNA interference (RNAi) exploits a mechanism of gene regulation whereby double-stranded RNAs are processed by a conserved cellular machinery to suppress the expression of genes containing homologous sequences (5). Importantly, libraries of DNA-based vectors encoding short hairpin RNAs (shRNAs) capable of targeting most genes in the human and mouse genomes have been produced and enable forward genetic screens to be performed in mammalian cells. Indeed, by using human tumor-derived cell lines treated in vitro, RNAi has been used to evaluate potential drug targets (6) or to investigate mechanisms of drug action and drug resistance by screening for new molecules that modulate the response of tumor-derived cell lines to a given chemotherapeutic agent (7-10).Here, we evaluate the suitability of combining mouse models and RNAi to identify genetic modifiers of drug action in tumors in their natural site. Initially, we chose to investigate resistance to doxorubicin in the E -Myc mouse lymphoma system. Doxorubicin (Adriamycin) is an anthracycline DNA-damaging agent that exerts its effects primarily by targeting of the topoisomerase 2 activity and DNA intercalation (11). Along with etoposide and the camptothecin derivatives, doxorubicin is one of several t...

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Section: Discussionmentioning

confidence: 69%

Topoisomerase levels determine chemotherapy response in vitro and in vivo

Burgess

Doles²,

Zender

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

278

236

View full text Add to dashboard Cite

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“…This observation suggested that ICL might be utilized as targeted therapy for BRCA1-mutant breast and ovarian cancers. Breast cancers that arose in mice engineered to have tissue-specific knockout of Brca1 and p53 are exquisitely sensitive to treatment with platinum compounds (Rottenberg et al, 2007). Moreover, these BRCA1 2/2 tumors did not develop resistance to despite repeated treatments and late recurrences remained platinum sensitive (Rottenberg et al, 2007).…”

Section: Brca1 and Dna Repairmentioning

confidence: 99%

BRCA1, PARP, and 53BP1: conditional synthetic lethality and synthetic viability

Aly¹,

Ganesan²

2011

Journal of Molecular Cell Biology

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BRCA1 plays a critical role in the regulation of homologous recombination (HR)-mediated DNA double-strand break repair. BRCA1-deficient cancers have evolved to tolerate loss of BRCA1 function. This renders them vulnerable to agents, such as PARP inhibitors, that are conditionally 'synthetic lethal' with their underlying repair defect. Recent studies demonstrate that BRCA1-deficient cells may acquire resistance to these agents by partially correcting their defect in HR-mediated repair, either through reversion mutations in BRCA1 or through 'synthetic viable' loss of 53BP1. These findings and their clinical implications will be reviewed in this article.

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“…With regard to this time issue, conditional Brca1 mouse models that develop mammary tumours with strong resemblance to human BRCA1-mutated breast tumours McCarthy et al, 2007) can be very helpful in predicting response and resistance to conventional and targeted therapeutics. Our K14cre;Brca1 F5 -13/F5 -13 ;Trp53 F2 -10/F 2 -10 mouse model was used for studying responses to various conventional chemotherapeutics, such as doxorubicin, docetaxel and cisplatin, and for analysing the mechanisms of acquired resistance (Rottenberg et al, 2007). Similar to the human situation, heterogeneity in the response of individual mouse mammary tumours was observed, but eventually all tumours became resistant to doxorubicin and docetaxel.…”

Section: Chemotherapeutic Interventions In Brca1 Modelsmentioning

confidence: 99%

“…This rapid recurrence could suggest the existence of a population of platinum-resistant cells that are selected during a second round of platinum treatment. An important difference between the two studies described above is that Rottenberg et al (2007) used a mouse model with a conditional Brca1 null allele, whereas Shafee et al (2008) used a Brca1 hypomorphic allele that still expresses the Brca1-D11 isoform after Cre-mediated deletion of exon 11. Furthermore, the platinum treatment regime differs considerably between the two studies.…”

Section: Chemotherapeutic Interventions In Brca1 Modelsmentioning

confidence: 99%

“…Rottenberg et al (2007Rottenberg et al ( , 2008 showed that upregulation of drug efflux pumps is the most prevalent mechanism of acquired resistance to conventional and targeted therapies for mammary tumours arising in the K14cre;Brca1 F5 -13/F5 -13 ;Trp53 F2 -10/F2 -10 mouse model. Currently, the treatment responses in this K14cre;Brca1 F/F ;Trp53 F/F mouse model are being studied in a Pglycoprotein-deficient background to unravel P-glycoproteinindependent mechanisms of drug resistance (Table 2).…”

Section: Next-generation Brca1 Modelsmentioning

confidence: 99%

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Preclinical mouse models for BRCA1-associated breast cancer

Drost

Jonkers

2009

Br J Cancer

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A substantial part of all hereditary breast cancer cases is caused by BRCA1 germline mutations. In this review, we will discuss the insights into BRCA1 functions that we obtained from mouse models with conventional and conditional mutations in Brca1. The most advanced models closely resemble human BRCA1-related breast cancer and may therefore be useful for addressing clinically relevant questions. Breast cancer is by far the most frequent cancer in women, accounting for over 20% of all cancer cases. Familial breast cancers, including those associated with heterozygous germline mutations in the major susceptibility genes BRCA1 and BRCA2, account for 5 -10% of breast cancer cases in the western world. BRCA1 mutation carriers have a lifetime risk of about 80% for developing breast cancer and a 40% lifetime risk for developing ovarian cancer. Most BRCA1-associated tumours show loss of heterozygosity (LOH) at the BRCA1 locus, leading to loss of the wild-type allele, which is consistent with a tumour suppressor function of BRCA1 (Narod and Foulkes, 2004).Since the discovery of the BRCA1 gene in 1994 (Miki et al, 1994), several genetically engineered mouse models have been generated for studying the in vivo functions of BRCA1. Initial studies used conventional knockout mice with germline mutations in the mouse Brca1 gene. These conventional Brca1 mouse mutants have enabled us to learn a lot about the biological roles of BRCA1. Because of the embryonic lethality of homozygous animals carrying two defective Brca1 alleles and the lack of mammary tumour development in heterozygous mice carrying one defective and one wild-type Brca1 allele, these models could not be used to study the role of BRCA1 in tumorigenesis. To overcome these problems, the investigators generated conditional Brca1 knockout mice that enable tissue-specific inactivation of BRCA1 by Cre recombinase-mediated deletion of one or more Brca1 exons flanked by loxP recombination sites (Jonkers and Berns, 2002). The most recently developed conditional Brca1 mammary tumour models closely mimic several important aspects of human BRCA1-associated breast cancer and therefore serve as important tools for the development of novel therapies for this disease. Before elaborating on the Brca1 conventional and conditional mouse models that have been generated to date, we will discuss the characteristics of human BRCA1-related breast cancer in more detail.

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Selective induction of chemotherapy resistance of mammary tumors in a conditional mouse model for hereditary breast cancer

Cited by 273 publications

References 47 publications

Topoisomerase levels determine chemotherapy response in vitro and in vivo

Topoisomerase levels determine chemotherapy response in vitro and in vivo

BRCA1, PARP, and 53BP1: conditional synthetic lethality and synthetic viability

Preclinical mouse models for BRCA1-associated breast cancer

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