Publication Date




Embargo Period


Degree Type


Degree Name

Doctor of Philosophy (PHD)


Cancer Biology (Medicine)

Date of Defense


First Committee Member

Karoline J. Briegel

Second Committee Member

Anthony Capobianco

Third Committee Member

Dorraya El-Ashry

Fourth Committee Member

Merce Jorda

Fifth Committee Member

Ralf Landgraf


Clinically aggressive basal-like triple negative breast cancers (B-TNBC) disproportionally contribute to cancer deaths, but lack effective treatment options due to absence of expression of key therapeutic targets. New evidence suggests that B-TNBC 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 the development of B-TNBC remain poorly understood. Our laboratory has identified a novel WNT/ß-Catenin target and transcriptional regulator, Limb-Bud-and Heart (LBH), which is majorly overexpressed in aggressive B-TNBC harboring WNT hyperactivation. We previously showed in vivo that LBH is a key stem cell and basal 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 B-TNBC formation and progression. 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 volume or burden were not changed, indicating that LBH is not required for WNT-driven tumorigenesis. Ubiquitous Lbh ablation delayed tumor onset even more drastically without affecting tumor volume. LBH-deficient MMTV-Wnt1-transgenic tumors did not exhibit significant histopathological differences compared to LBH WT MMTV-Wnt1-transgenic tumors; Whereas MMTVWnt1+; K14Cre;Lbh WT tumors were highly vascularized, disorganized, with mixed basal and luminal cell identity; tumors from MMTV-Wnt1+;K14Cre;Lbh KO mice were more organized, differentiated, and predominantly luminal Keratin 8 positive. The attenuation of mammary gland hyperplasia and tumor onset suggested that LBH deficiency may negatively affect WNT-induced stem cell expansion, which we were able to confirm in vitro using human breast cancer cell lines and in vivo using a transgenic GFP-reporter line. We also confirmed that LBH overexpression caused a luminal-to-basal conversion using a human breast cancer cell line. Our data indicate that LBH is an essential cell fate regulator downstream of WNT signaling that maintains basal lineage identity in B-TNBC. LBH inhibition may be a potential novel strategy to treat B-TNBC patients through differentiation therapy.


cancer biology, molecular biology, breast cancer, triple negative breast cancer, Wnt, LBH

Available for download on Friday, May 07, 2021