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24Jun 2016

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New mouse model platform for invasive lobular breast cancer allows rapid in vivo testing of potential cancer genes


Large-scale genetic screens have in recent years identified many genes that potentially are drivers behind tumor formation. To determine whether they are indeed true cancer genes, in vivo testing in reliable animal models of human cancer is essential. The team of Jos Jonkers at the Netherlands Cancer Institute has developed a technique for creating mouse models for invasive lobular carcinoma (ILC) that doesn't require lengthy breeding of transgenic mice. They describe their approach in the journal Genes & Development.

Invasive lobular carcinoma is the second most common type of breast cancer, accounting for 8-14 percent of all human breast cancer cases. It can be modeled in mice, but this requires a complex breeding process to create transgenic mice with multiple mutations. Therefore, easier ways to create mouse models for ILC are more than welcome. The team of Jos Jonkers tried a new approach: they injected lentiviral vectors in the mammary glands of adult mice. They also tried a CRISPR/Cas9 approach and a technique that combined both approaches.

Intraductal injection of Cre-encoding lentiviruses turned out to indeed induce ILC in mice harboring, together with conditional Cdh1 alleles, a conditional Akt-E17K mutation or conditional Pten alleles. Somatic gene editing by intraductal injection of CRISPR/Cas9 lentiviruses also induced tumor formation, but it resulted in mammary tumors that did not resemble ILC. This was most likely caused by a Cas9-specific immune response, as shown by the strong immune infiltrate. In contrast, intraductal injection of CRISPR lentiviruses in mice with mammary-specific expression of Cas9 was successful in inducing ILC.

"Our platform allows for accelerated creation of novel ILC mouse models, with tumors that are indistinguishable from the ones in our original transgenic mouse models and from human ILC.", says Jonkers. "It simplifies the breeding procedure and also allows for spatiotemporal control of the initiation of the tumors. In contrast, in the transgenic mouse models, the mutations are already active during pre-pubertal development. Plus, while transgenic mice often develop mammary tumors in multiple glands, we can restrict tumor induction to a single gland."

According to Jonkers, their techniques could in principle be extended to other types of breast cancer. This would make in vivo testing of putative cancer genes easier not only for ILC, but also for these other types of cancer.

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