The Embryonic Transcription Cofactor LBH Is a Direct Target of the Wnt Signaling Pathway in Epithelial Development and in Aggressive Basal Subtype Breast Cancers

Rieger, Megan E.; Sims, Andrew H.; Coats, Ebony; Clarke, Robert B.; Briegel, Karoline J.

doi:10.1128/mcb.01418-09

Cited by 84 publications

(116 citation statements)

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“…We hypothesize that in ER-positive patients with an inactive ER pathway, other pathways such as Wnt or Hedgehog, associated with more aggressive behavior and worse outcome, may actually have been driving tumor growth (1,54,55). This is in agreement with the reported decline in SET index with advancing pathologic cancer stage, despite ER positivity, suggesting decreasing tumor dependency on an active ER pathway (53).…”

Section: Discussionsupporting

confidence: 81%

Selection of Personalized Patient Therapy through the Use of Knowledge-Based Computational Models That Identify Tumor-Driving Signal Transduction Pathways

et al. 2014

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Increasing knowledge about signal transduction pathways as drivers of cancer growth has elicited the development of "targeted drugs," which inhibit aberrant signaling pathways. They require a companion diagnostic test that identifies the tumor-driving pathway; however, currently available tests like estrogen receptor (ER) protein expression for hormonal treatment of breast cancer do not reliably predict therapy response, at least in part because they do not adequately assess functional pathway activity. We describe a novel approach to predict signaling pathway activity based on knowledge-based Bayesian computational models, which interpret quantitative transcriptome data as the functional output of an active signaling pathway, by using expression levels of transcriptional target genes. Following calibration on only a small number of cell lines or cohorts of patient data, they provide a reliable assessment of signaling pathway activity in tumors of different tissue origin. As proof of principle, models for the canonical Wnt and ER pathways are presented, including initial clinical validation on independent datasets from various cancer types. Cancer Res; 74(11); 2936-45. Ó2014 AACR.

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Section: Discussionsupporting

confidence: 81%

Selection of Personalized Patient Therapy through the Use of Knowledge-Based Computational Models That Identify Tumor-Driving Signal Transduction Pathways

et al. 2014

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“…These findings are highly significant given that in human breast cancer, LBH is aberrantly overexpressed in the most lethal basal tumor subtype (Lamb et al, 2013;Rieger et al, 2010), which is hormone receptor negative and enriched in cancer stem cells (Honeth et al, 2008;Sorlie et al, 2003). Future studies will be necessary to elucidate the precise mechanism by which LBH regulates basal MaSC function and its role in carcinogenesis, as well as to determine its contribution to the stem cell-promoting effects of WNT in normal and neoplastic mammary gland development.…”

Section: Discussionmentioning

confidence: 86%

“…Reduced cell proliferation in TEBs and alveoli of pubertal or pregnant K14-Cre;Lbh loxP/loxP glands, respectively, further suggests that LBH is required for MaSC activation, as these lobular structures are normally enriched in actively proliferating MaSCs (Bai and Rohrschneider, 2010;Williams and Daniel, 1983) and express high levels of LBH Rieger et al, 2010). Although it remains debatable whether unipotent basal and luminal stem cells alone or multi-potent basal MaSCs generate mammary gland epithelium in vivo (van Amerongen et al, 2012;Van Keymeulen et al, 2011;Prater et al, 2014;Rios et al, 2014), in situ stem cell marker analyses (Williams and Daniel, 1983) and in vivo labeling of activated MaSCs using a transgenic SHIP-GFP reporter line (Bai and Rohrschneider, 2010) suggest that activated MaSCs have basal characteristics, including a CD29 lo CD24 + marker profile.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, LBH is aberrantly overexpressed in breast tumors of MMTV-Wnt1 transgenic mice , which are enriched in basal MaSCs . Importantly, LBH is abnormally overexpressed in worst prognosis hormone receptor-negative human breast cancers of the 'basal' molecular subtype, correlating with WNT pathway hyperactivation (Lamb et al, 2013;Rieger et al, 2010). The strong association between LBH expression and canonical WNT signaling in both normal and cancerous breast tissues prompted us to further explore the role of LBH in mammary epithelial development.…”

Section: /Sca1mentioning

confidence: 99%

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The WNT-controlled transcriptional regulator LBH is required for mammary stem cell expansion and maintenance of the basal lineage

et al. 2015

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The identification of multipotent mammary stem cells (MaSCs) has provided an explanation for the unique regenerative capacity of the mammary gland throughout adult life. However, it remains unclear what genes maintain MaSCs and control their specification into the two epithelial lineages: luminal and basal. LBH is a novel transcription co-factor in the WNT pathway with hitherto unknown physiological function. LBH is expressed during mammary gland development and aberrantly overexpressed in aggressive 'basal' subtype breast cancers. Here, we have explored the in vivo role of LBH in mammopoiesis. We show that in postnatal mammary epithelia, LBH is predominantly expressed in the Lin − CD29high CD24 + basal MaSC population. Upon conditional inactivation of LBH, mice exhibit pronounced delays in mammary tissue expansion during puberty and pregnancy, accompanied by increased luminal differentiation at the expense of basal lineage specification. These defects could be traced to a severe reduction in the frequency and self-renewal/ differentiation potential of basal MaSCs. Mechanistically, LBH induces expression of key epithelial stem cell transcription factor ΔNp63 to promote a basal MaSC state and repress luminal differentiation genes, mainly that encoding estrogen receptor α (Esr1/ERα). Collectively, these studies identify LBH as an essential regulator of basal MaSC expansion/maintenance, raising important implications for its potential role in breast cancer pathogenesis.

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“…In the early stage of vertebrate embryogenesis, LBH regulates the formation of the limbs and heart. Moreover, Rieger et al reported that the WNT signaling pathway can directly target LBH to participate in the occurrence and development of breast cancer [10]. Liu et al showed that nasopharyngeal epithelial cells may initiate malignant transformation due to the Epstein-Barr virus-mediated downregulation of LBH [11].…”

Section: Introductionmentioning

confidence: 99%

Limb-Bud and Heart Attenuates Growth and Invasion of Human Lung Adenocarcinoma Cells and Predicts Survival Outcome

Deng

Wang

et al. 2018

Cell Physiol Biochem

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Background/Aims: The transcription cofactor limb-bud and heart (LBH) is involved in embryonic development. However, its role in human lung cancer, especially lung adenocarcinoma (LUAD), remains unclear. Methods: A public database and tissue microarray (TMA) were used to compare differences in LBH expression and its relationship with clinical characteristics. Tissue from an additional 70 LUAD patients with follow-up records was used to explore the correlation of LBH expression with prognosis. Cellular and molecular studies validated the role of LBH in LUAD growth and invasion. Results: LBH was significantly down-regulated in lung cancer tissue samples and was correlated with the prognosis and clinical characteristics of lung cancer patients based on a public database and TMA. Survival analysis revealed that LBH-negative expression was associated with poor overall survival of LUAD patients (P = 0.021). Cox regression analysis showed that LBH expression status was a favorable independent prognostic factor (hazard ratio = 0.120, 95% confidence interval = 0.016–0.894, P = 0.039). LBH knockdown accelerated LUAD cell proliferation, migration, and invasion. Furthermore, bioinformatics analysis indicated that LBH was significantly related to the cell adhesion pathway. Western blot analysis confirmed that LBH could regulate the expression of integrin family members (integrin-α1, integrin-α2, integrin-α4, integrin-αv, and integrin-β4). Conclusion: Our data suggest that LBH plays an important role in lung cancer. Importantly, LBH is an independent prognostic factor in LUAD and can attenuate cell growth and invasion. LBH may be a potential prognostic biomarker in LUAD patients.

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The Embryonic Transcription Cofactor LBH Is a Direct Target of the Wnt Signaling Pathway in Epithelial Development and in Aggressive Basal Subtype Breast Cancers

Abstract: Limb-bud and heart (LBH) is a novel key transcriptional regulator of vertebrate development. However, the molecular mechanisms upstream of LBH and its role in adult development are unknown. Here we show that in epithelial development, LBH expression is tightly controlled by Wnt signaling.

Cited by 84 publications

References 78 publications

Selection of Personalized Patient Therapy through the Use of Knowledge-Based Computational Models That Identify Tumor-Driving Signal Transduction Pathways

Selection of Personalized Patient Therapy through the Use of Knowledge-Based Computational Models That Identify Tumor-Driving Signal Transduction Pathways

The WNT-controlled transcriptional regulator LBH is required for mammary stem cell expansion and maintenance of the basal lineage

Limb-Bud and Heart Attenuates Growth and Invasion of Human Lung Adenocarcinoma Cells and Predicts Survival Outcome

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