The 8p11-p12 genomic region is amplified in 15% of breast cancers and is associated with poorer prognosis. This genomic region harbors several oncogenes, including three epigenetic chromatin modifiers: ASH2L, KAT6A, and WHSC1L1. WHSC1L1 is a histone methyltransferase expressed in two isoforms and we have previously demonstrated that this oncogene is involved in overexpression of ERá as well as its activation independent of estrogen signaling in amplicon-bearing SUM44 breast cancer cells. This cell line serves as a model for the subset of breast cancer patients who demonstrate resistance to hormonal therapies in the context of the 8p11 amplicon and WHSC1L1 overexpression. To validate the connection between overexpression of WHSC1L1 and ESR1, we specifically overexpressed the short, non-catalytic isoform of WHSC1L1 in amplicon-bearing cell lines without WHSC1L1 overexpression. Overexpression of WHSC1L1-short resulted in increased expression of ERá in CAMA1 and SUM52 cells, but not in the amplicon null MCF7 cells. To analyze further the oncogenic role of WHSC1L1 in breast cancer, we generated a transgenic mouse model with targeted overexpression of WHSC1L1 in the mammary gland of FVB/N mice. WHSC1L1 transgenic females had normal sized litters, however the pups were profoundly underdeveloped compared to pups born to wild-type females. Pups born to transgenic females displayed delayed hair growth and eye opening and were half the weight of healthy pups nursed by wild-type females. This suggested a lactation deficiency in WHSC1L1-transgenic females. To further investigate this phenotype, mammary glands were harvested for histologic analysis from transgenic and wild-type females at various stages of the reproductive cycle. Mammary glands from virgin WHSC1L1 transgenic females displayed increased branching and terminal bud formation compared to wild-type virgin females. Similarly, alveolar buds of mid-pregnant females were more numerous and densely packed than in wild-type mice. Consistent with a lactation defect, mammary glands from lactating transgenic females showed evidence of decreased alveolar development compared to wild-type females, resulting in mammary glands where half of the gland failed to functionally differentiate. Finally, post-lactation mammary glands from wild-type females underwent involution, whereas glands from transgenic females failed to involute and were hyperplastic. Significantly, we have observed mammary tumor formation in two transgenic female mice thus far. Ongoing studies include further characterization of this novel mouse model, investigation of the effects of WHSC1L1 overexpression on mammary gland development as pertaining to breast cancer tumorigenesis, and the oncogenic role of WHSC1L1 and its effects on ERá. These and other studies are essential for understanding WHSC1L1 and the 8p11 amplicon in ER+ breast cancer, and how this genomic alteration can be exploited to improve patient outcomes.

Citation Format: Brittany Turner Ivey. WHSC1L1 is a driving oncogene in ERá positive breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 674.