Abstract P4-05-01: Limb-Bud-and-Heart (LBH), a novel WNT effector in promoting basal-like breast cancer

BACKGROUND: Clinically aggressive basal-like breast cancers (BLBC) disproportionally contribute to cancer deaths, but lack effective treatment options due to absence of expression of key therapeutic targets (i.e. ER, PR, HER2). New evidence suggests BLBC may originate from luminal breast epithelial cells through luminal-to-basal cell lineage conversion and dedifferentiation. However, the factors that reprogram cell fate and differentiation states during BLBC development remain poorly understood. Our laboratory has identified a novel WNT/β-Catenin target transcriptional regulator, Limb-Bud-and-Heart (LBH), and shown LBH is majorly over expressed in aggressive BLBC harboring WNT hyperactivation. We previously showed in genetic mouse models in vivo that LBH is a key mammary stem cell and basal cell lineage regulator essential for normal mammary gland development. Using crosses between MMTV-Wnt1 transgenic mice and conditional LBH knockout mice, we tested if LBH is a critical effector of WNT-driven basaloid breast cancer, and whether its inhibition may prevent and/or attenuate BLBC formation and progression. RESULTS: In our in vivo mouse model, LBH inactivation in the basal mammary epithelium using a Keratin 14/K14-Cre deleter strain significantly attenuated MMTV-Wnt1-induced mammary gland hyperplasia and led to a delay in tumor onset. Surprisingly, tumor burden and tumor volumes were not changed, indicating that LBH is not required for WNT-driven tumorigenesis. However, LBH-deficient MMTV-Wnt1-transgenic tumors exhibited pronounced histopathological differences compared to LBH WT MMTV-Wnt1-transgenic tumors. Whereas MMTV-Wnt1+;K14CreLbh WT tumors were highly vascularized, disorganized, with mixed basal and luminal cell identity; tumors from MMTV-Wnt1+;K14CreLbh KO mice were more organized, differentiated, and predominantly luminal Keratin 8 positive. Since attenuation of mammary gland hyperplasia and tumor onset in this model suggests that LBH deficiency may negatively affect WNT-induced stem cell expansion, we next investigated the LBH effects on the tumor stem cell compartment. MMTV-Wnt1+;K14CreLbh KO mice were crossed with two different stem cell reporter lines: Lgr5-eGFP mice, which specifically mark WNT-responsive epithelial stem cells; and SHIP-GFP reporter mice, which mark activated, proliferating mammary stem cells but not quiescent or slow-cycling stem cells. These studies are ongoing and the latest findings will be discussed. CONCLUSION: Our data indicate that LBH is an essential cell fate regulator downstream of oncogenic WNT signaling that maintains basal lineage identity in baseloid breast cancers. LBH inhibition may be a potential novel strategy to treat basal subtype triple negative breast cancer patients through differentiation therapy. Citation Format: Briegel K, Ashad-Bishop K. Limb-Bud-and-Heart (LBH), a novel WNT effector in promoting basal-like breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-05-01.