Abstract 1835: Development of mammary hyperplasia, dysplasia, and invasive ductal carcinoma in transgenic mice expressing the 8p11 amplicon oncogene NSD3 (WHSC1L1)
Authors: Rutkovsky Alex C. , Turner-Ivey Brittany , Smith Ericka L. , Spruill Laura S. , Mills Jamie N. , Ethier Stephen P. 
Published: July 2017

Abstract
Amplification within the 8p11-12 locus occurs in approximately 15% of breast cancer (BC) and is associated with poor survival and distant recurrence. Overexpression of many of the genes within the 8p11-12 region can confer a pathological gain of function to breast cells. We and others have previously demonstrated that NSD3 (WHSC1L1), a lysine methyltransferase, can act as a potent transforming oncogene. Predictions by the GISTIC algorithm of the Human Cancer Genome Atlas data suggest that NSD3 is a driving gene within 8p11-12 in multiple tumor types, including BC. We previously showed that NSD3 can regulate the expression of influential genes, such as estrogen receptor alpha (ESR1/ERα). To further explore the role of NSD3 in promoting BC, we generated FVB/N transgenic mice with targeted overexpression of NSD3 in the mammary gland and compared them to matched non-transgenic wild-type (WT) females. We observed that pups nursed by transgenic females were underdeveloped, regardless of genotype. Underdeveloped pups displayed delayed hair growth and eye opening, and were half the weight of pups nursed by WT females. To investigate this phenotype, we characterized thoracic and inguinal mammary glands from virgin, mid-pregnancy, lactating, and post-lactating mice by whole mount and histological analysis. Mammary glands from virgin transgenic females displayed increased branching and terminal bud formation. Alveolar buds from mid-pregnant transgenic glands were more numerous and densely packed. Glands from lactating transgenic females showed large areas in which the alveoli failed to undergo functional differentiation, resulting in a lactation defect. Mammary glands taken post-lactation exhibited areas of ductal and alveolar hyperplasia. At 40 weeks of age, multiple transgenic mice had palpable tumors which were excised at 1 cm3 size. Whole mount and histological analysis of glands from tumor bearing mice commonly demonstrated hyperplasia, dysplasia, and carcinoma in situ, contrary to age-matched WT glands. The areas of ductal dysplasia and carcinoma in situ closely resembled several patterns commonly observed in human breast cancer, including micropapillary, cribriform, and high grade areas of ductal carcinoma in situ. Mammary tumors were analogous to infiltrating ductal carcinomas, many of which were high grade tumors. In summary, overexpression of NSD3 in the mouse mammary gland elicited drastic deformation, inhibited functional differentiation, and caused tumor formation. Continued characterization of this mouse model, the oncogenic role of NSD3, and other mechanistic studies are essential to improve patient outcome in 8p11-12 altered cancers.
Citation Format: Alex C. Rutkovsky, Brittany Turner-Ivey, Ericka L. Smith, Laura S. Spruill, Jamie N. Mills, Stephen P. Ethier. Development of mammary hyperplasia, dysplasia, and invasive ductal carcinoma in transgenic mice expressing the 8p11 amplicon oncogene NSD3 (WHSC1L1) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1835. doi:10.1158/1538-7445.AM2017-1835