Mutating E-cadherin in rats to model lobular breast cancer

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This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-23-045.”The parent award R01CA271498 is focused on studying rat models of ductal breast cancer, but it does not study invasive lobular breast cancer (ILC), which accounts for up to 40,000 cases yearly in the US. ILC is predominantly estrogen receptor-positive (ER+). Loss of E-cadherin (encoded by the CDH1 gene) is the pathognomonic feature of ILC being lost at the protein level in over 95% of cases, while mutations of CDH1 occur in 65% of cases. Genetic loss of CDH1 has not been engineered into rat mammary gland cells for studying ILC, but we now have the technical capabilities to engineer CDH1 mutations into rat mammary glands. We predict that CDH1 loss will predispose rat mammary glands for ER+ ILC. In this supplement award, we will team up with the Oesterreich-Lee laboratory, which has extensive expertise in studying ILC, using human specimens, cell culture, and organoids of carcinogen-induced rat tumors. The goal is to develop a clinically relevant rat model of ER+ ILC. Two specific aims are pursued: Aim 1: Examine the effect of somatic CDH1 deletion on rat mammary gland development and function. This somatic CDH1 KO will be achieved using our recently published method using intraductal injection of virus for high efficiency in vivo CRISPR- genome editing. Aim 2: Test whether the combination of somatic CDH1 deletion and PIK3CA activation or DMBA treatment results in rat ER+ mammary tumors with a histopathology and gene expression similar to human ILC. We select the combination of CDH1 KO and PIK3CA activation because CDH1 KO alone is unlikely to sufficient to cause cancer and because PIK3CA is the protooncogene most commonly mutated in human breast cancer including ILC.