Abstract PR003: Pioneering genetic rat models of Ductal Carcinoma in situ (DCIS)

Abstract

Abstract DCIS has been virtually unknown before the introduction of breast cancer screening programs in the 1980s. Since then, its incidence has been rising steeply and it now accounts for about 25% of all newly diagnosed ‘breast cancer’ cases. Despite the increase in occurrence, the molecular underpinnings regulating DCIS initiation and progression remain elusive. In addition, almost all DCIS cases are hormone dependent, a characteristic which remains one of the biggest challenges to recapitulate in breast cancer research. We could successfully establish models for DCIS as well as estrogen receptor positive disease subtypes by somatically engineering the rat mammary gland via intraductal injection of lentiviral vectors encoding for the most commonly mutated genes (Ccnd1, Myc, Pik3ca and p53) in (pre-) breast cancer. Models with one perturbed gene remained mostly mammary tumor-free after an observation period of 18 months. However, when perturbed in two loci, animals showed mammary lesion formation within 5 and after up to 40 weeks. Histopathological analysis of these lesions characterized a broad spectrum of tumor types including ductal and lobular carcinomas, with both in situ and invasive phenotypes. Among these tumor types, DCIS lesions as well as invasive ductal carcinoma showed estrogen receptor positivity after immunohistochemical staining. Two distinct growth patterns were observed: a flat growing tumor, shaped by, and replacing the host rat mammary duct, and a round growing lesion, disregarding ductal structures. Interestingly, the flat growing tumor pattern evolved mostly in models expressing luminal drivers (Ccnd1 and Pik3ca) and strongly correlated with in situ growth. To increase luminal subtypes and to narrow down the broad tumor spectrum observed in these models, we generated a luminal cell type-specific promoter expressing our genes of interest. Pathological analysis of the arisen tumors indeed revealed a more homogeneous tumor subtype for all models, with an average tumor latency of 28 to 40 weeks. These genetically engineered models for DCIS and estrogen receptor positive breast cancer may aid in an improved treatment stratification by distinguishment between indolent and aggressive DCIS, a persisting challenge as of today. Additionally, these models broaden the scope of available hormone dependent breast cancer models, benefitting the search for novel treatment regiments for patients suffering from this breast cancer subtype. Citation Format: Catrin Lutz, Madelon Badoux, Timo Eijkman, Bim de Klein, Ji-Ying Song, Linda Henneman, Colinda Scheele, Jelle Wesseling, Jos Jonkers. Pioneering genetic rat models of Ductal Carcinoma in situ (DCIS) [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr PR003.