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.