LBH is a cancer stem cell- and metastasis-promoting oncogene essential for WNT stem cell function in breast cancer

Garikapati, Koteswara Rao; Ashad-Bishop, Kilan C.; Hong, Sunhwa; Qureshi, Rehana; Rieger, Megan E.; Lindley, Linsey E.; Wang, Bin; Azzam, Diana J.; Khanlari, Mahsa; Nadji, Mehrad; Jain, Chaitanya; Kwon, Deukwoo; Ban, Yuguang; Chen, Steven; Sims, Andrew H.; Kesmodel, Susan B.; Slingerland, Joyce M.; Briegel, Karoline J.

doi:10.1101/2021.01.29.428659

Cited by 3 publications

(1 citation statement)

References 68 publications

(151 reference statements)

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“…Limb-Bud-and-Heart (LBH) is a co-transcription factor of Wnt/β-catenin target genes that participates in activating the stem cell transcription program in breast cancer cells, further leading to cancer metastasis. Previous research has shown that inhibition of Cadherin 11 (CDH11)the expression of which is correlated with shorter survival in TNBC-can downregulate β-catenin, which suppresses the canonical Wnt signaling pathway, thereby inhibiting the cancer stem-like phenotype in TNBC [49][50][51]. Several recent studies have proved XB130 overexpression in malignancies.…”

Section: Intrinsic Molecular Activities Of Bcscsmentioning

confidence: 99%

Breast Cancer Stem Cells: Signaling Pathways, Cellular Interactions, and Therapeutic Implications

Wang

Zeng

Master

et al. 2022

Cancers

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Breast cancer stem cells (BCSCs) constitute a small population of cells within breast cancer and are characterized by their ability to self-renew, differentiate, and recapitulate the heterogeneity of the tumor. Clinically, BCSCs have been correlated with cancer progression, metastasis, relapse, and drug resistance. The tumorigenic roles of BCSCs have been extensively reviewed and will not be the major focus of the current review. Here, we aim to highlight how the crucial intrinsic signaling pathways regulate the fate of BCSCs, including the Wnt, Notch, Hedgehog, and NF-κB signaling pathways, as well as how different cell populations crosstalk with BCSCs within the TME, including adipocytes, endothelial cells, fibroblasts, and immune cells. Based on the molecular and cellular activities of BCSCs, we will also summarize the targeting strategies for BCSCs and related clinical trials. This review will highlight that BCSC development in breast cancer is impacted by both BCSC endogenous signaling and external factors in the TME, which provides an insight into how to establish a comprehensively therapeutic strategy to target BCSCs for breast cancer treatments.

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Section: Intrinsic Molecular Activities Of Bcscsmentioning

confidence: 99%

Breast Cancer Stem Cells: Signaling Pathways, Cellular Interactions, and Therapeutic Implications

Wang

Zeng

Master

et al. 2022

Cancers

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Multi-cancer analysis reveals universal association of oncogenic LBH expression with DNA hypomethylation and WNT-Integrin signaling pathways

et al. 2023

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Limb-Bud and Heart (LBH) is a developmental transcription co-factor deregulated in cancer, with reported oncogenic and tumor suppressive effects. However, LBH expression in most cancer types remains unknown, impeding understanding of its mechanistic function Here, we performed systematic bioinformatic and TMA analysis for LBH in >20 different cancer types. LBH was overexpressed in most cancers compared to normal tissues (>1.5-fold; p < 0.05), including colon-rectal, pancreatic, esophageal, liver, stomach, bladder, kidney, prostate, testicular, brain, head & neck cancers, and sarcoma, correlating with poor prognosis. The cancer types showing LBH downregulation were lung, melanoma, ovarian, cervical, and uterine cancer, while both LBH over- and under-expression were observed in hematopoietic malignancies. In cancers with LBH overexpression, the LBH locus was frequently hypomethylated, identifying DNA hypomethylation as a potential mechanism for LBH dysregulation. Pathway analysis identified a universal, prognostically significant correlation between LBH overexpression and the WNT-Integrin signaling pathways. Validation of the clinical association of LBH with WNT activation in gastrointestinal cancer cell lines, and in colorectal patient samples by IHC uncovered that LBH is specifically expressed in tumor cells with nuclear beta-catenin at the invasive front. Collectively, these data reveal a high degree of LBH dysregulation in cancer and establish LBH as pan-cancer biomarker for detecting WNT hyperactivation in clinical specimens.

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Transcription co-factor LBH is necessary for the survival of cochlear hair cells

Liu

Giffen

Grati

et al. 2021

Journal of Cell Science

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Hearing loss affects ∼10% adults worldwide. Most sensorineural hearing loss is caused by progressive loss of mechanosensitive hair cells (HCs) in the cochlea. The molecular mechanisms underlying HC maintenance and loss remain poorly understood. LBH, a transcription co-factor implicated in development, is abundantly expressed in outer hair cells (OHCs). We used Lbh-null mice to identify its role in HCs. Surprisingly, Lbh deletion did not affect differentiation and early development of HCs, as nascent HCs in Lbh knockout mice had normal looking stereocilia. The stereocilia bundle was mechanosensitive and OHCs exhibited the characteristic electromotility. However, Lbh-null mice displayed progressive hearing loss, with stereocilia bundle degeneration and OHC loss as early as postnatal day 12. RNA-seq analysis showed significant gene enrichment of biological processes related to transcriptional regulation, cell cycle, DNA damage/repair and autophagy in Lbh-null OHCs. In addition, Wnt and Notch pathway-related genes were found to be dysregulated in Lbh-deficient OHCs. Our study implicates, for the first time, loss of LBH function in progressive hearing loss, and demonstrates a critical requirement of LBH in promoting HC survival in adult mice.

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LBH is a cancer stem cell- and metastasis-promoting oncogene essential for WNT stem cell function in breast cancer

Cited by 3 publications

References 68 publications

Breast Cancer Stem Cells: Signaling Pathways, Cellular Interactions, and Therapeutic Implications

Breast Cancer Stem Cells: Signaling Pathways, Cellular Interactions, and Therapeutic Implications

Multi-cancer analysis reveals universal association of oncogenic LBH expression with DNA hypomethylation and WNT-Integrin signaling pathways

Transcription co-factor LBH is necessary for the survival of cochlear hair cells

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