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Modeling invasive lobular breast carcinoma by CRISPR/Cas9-mediated somatic genome editing of the mammary gland

06/15/2016

Modeling invasive lobular breast carcinoma by CRISPR/Cas9-mediated somatic genome editing of the mammary gland

Stefano Annunziato et al.

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

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 oncogenes, in vivo testing in reliable animal models of human cancer is essential. The team of Netherlands Cancer Institute researcher Jos Jonkers 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 June 15 issue of 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 a mouse model 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. CRISPR/Cas9 somatic editing 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, a combined lentiviral and Cas9 approach was successful in inducing ILC.

“Our platform allows for the more rapid creation of ILC mouse models, with tumors that are indistinguishable from the ones in the WapCre-driven transgenic mice model.”, says Jonkers. “It simplifies the breeding procedure and also allows for spatiotemporal control of the initiation of the tumors. In contrast, in the WapCre model, the mutations are already active during pre-puberal development stages. 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 oncogenes easier not only for ILC, but also for these other types of cancer.



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