Abstract P2-05-04: The WNT pathway gene, LBH, is critically required for breast carcinogenesis by promoting tumor initiation and survival

Abstract

Abstract Background: Cancer stem cells (CSCs) are a small subset of tumor cells with stem cell properties that drive tumor initiation, treatment resistance, and metastasis, thereby leading to rapid disease relapse. However, no cancer stem cell specific treatments are currently available in the clinic. Thus, there is a need to identify novel cancer stem cell-specific molecular targets. LBH (Limb-Bud and Heart), is a poorly characterized transcription co-factor in the WNT pathway, a signaling network that is key to normal stem cell control and cancer stem cell transformation. We previously identified LBH as a basal mammary stem cell specific marker critically required for stem cell self-renewal and maintenance during normal mammary gland development. Significantly, LBH is also abnormally over-expressed specifically in worst prognosis basal-like breast cancers, a treatment-resistant breast cancer subtype that is enriched in cancer stem cells. Moreover, high inter-tumor LBH expression levels correlate with reduced metastasis-free patient survival and increased chemo-resistance. However, the role of LBH in breast carcinogenesis is not known. Results: To identify the potential role of LBH in breast carcinogenesis, we abrogated LBH expression in breast cancer cell lines with high CSC populations (HCC1395, MDA-MB-231) using shRNA and CRISPR/Cas technologies. Conversely, we stably introduced LBH into more differentiated breast cancer cell lines with low CSC populations (MCF7, BT549). We found that LBH depletion significantly reduced, while LBH overexpression increased in vitro tumor sphere formation and clonogenic ability, suggesting LBH promotes a CSC phenotype. Modulation of LBH expression did not change proliferation rates, indicating the CSC promoting effects of LBH were not due to increased cell proliferation. However, LBH reduced apoptosis rates and increased tumor cell survival. Importantly, loss of LBH markedly decreased in vivo tumor initiation and metastatic potential of triple negative breast cancer cells, which are important functions of CSC. The underlying mechanisms will be discussed. Conclusions: Collectively our results suggest that LBH is required for breast CSC self-renewal and maintenance. Thus, LBH inhibition may have value for future CSC-targeted anti-cancer therapy. Citation Format: Garikapati K, Chen P, Ashad-Bishop K, Briegel K. The WNT pathway gene, LBH, is critically required for breast carcinogenesis by promoting tumor initiation and survival [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 P2-05-04.