A hedgehog pathway-dependent gene signature is associated with poor clinical outcomes in Luminal A breast cancer

Rudolph, Marion; Sizemore, Steven T.; Lu, Yuanzhi; Teng, Kun-Yu; Basree, Mustafa; Reinbolt, Raquel; Timmers, Cynthia; Leone, Gustavo; Ostrowski, Michael C.; Majumder, Sarmila; Ramaswamy, Bhuvaneswari

doi:10.1007/s10549-018-4718-x

Cited by 7 publications

(7 citation statements)

References 37 publications

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“…The authors also showed that the expression of the aforementioned factors was overexpressed in the patients with Luminal B and triple‐negative tumors, while the expression of SHH, DHH, and GLI1 correlates with poor survival 47 . In contrast to the results of our analysis, which revealed that a high expression of SHH, HHAT, PTCH1, GLI1 , and GLI2 , and GLI3 expression was associated with a better relapse‐free survival in the patients if not further stratified ( n = 3951), as well as if stratified for Luminal A ( n = 1933), Luminal B ( n = 1149), and basal‐like subtype ( n = 618), and partially also in lymph node‐positive tumors ( n = 1133), in other studies, the expression of these genes has been associated with a poor prognosis 19,48–52 . However, an important difference between our study and others is the number of analyzed patients and the methodology implemented (e.g., mRNA expression vs. immunohistochemistry [IHC]).…”

Section: Discussioncontrasting

confidence: 80%

“…52 Besides this, the co-expression of GLI1 with EGFR and SNAI1 was associated with poor distant disease-free survival in Luminal A tumors. 52 These data are very important and interesting because patients with the Luminal A subtype have a good prognosis, but some of them (14%) suffer from a disease recurrence within 3-5 years of diagnosis and have a risk of long-term recurrence. 51 Probably, the expression of GLI1 has some impact on the recurrence of these patients.…”

Section: Discussionmentioning

confidence: 98%

“…47 In contrast to the results of our analysis, which revealed that a high expression of SHH, HHAT, PTCH1, GLI1, and GLI2, and GLI3 expression was associated with a better relapsefree survival in the patients if not further stratified (n = 3951), as well as if stratified for Luminal A (n = 1933), Luminal B (n = 1149), and basal-like subtype (n = 618), and partially also in lymph node-positive tumors (n = 1133), in other studies, the expression of these genes has been associated with a poor prognosis. 19,[48][49][50][51][52] However, an important difference between our study and others is the number of analyzed patients and the methodology implemented (e.g., mRNA expression vs. immunohistochemistry [IHC]). For example, in a cohort of 279 patients, the staining of Hh ligand by IHC was analyzed.…”

Section: Discussionmentioning

confidence: 99%

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Prognostic significance of hedgehog signaling network‐related gene expression in breast cancer patients

Kuehn

Espinoza-Sánchez

Teixeira

et al. 2021

J of Cellular Biochemistry

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Breast cancer continues to be a serious public health problem. The role of the hedgehog pathway in normal development of the mammary gland as well as in carcinogenesis and progression of breast cancer is the subject of intense investigation, revealing functional interactions with cell surface heparan sulfate. Nevertheless, its influence on breast cancer prognosis, and its relation to specific sulfation motifs in heparan sulfate have only been poorly studied in large patient cohorts. Using the public database KMplotter that includes gene expression and survival data of 3951 patients, we found that the higher expression of SHH, HHAT, PTCH1, GLI1, GLI2, and GLI3 positively influences breast cancer prognosis. Stratifying patients according to the expression of hormone receptors, histological grade, lymph node metastasis, and systemic therapy, we observed that GLI1, GLI2, and GLI3 expression, as well as coexpression of SHH and ELP1 were associated with worse relapse-free survival in patients with HER2-positive tumors. Moreover, GLI1 expression in progesterone receptor-negative tumors and GLI3 expression in grade 3 tumors correlated with poor prognosis. SHH, in a panel of cell lines representing different breast cancer subtypes, and HHAT, PTCH1, GLI1, GLI2, and GLI3 were mostly expressed in cell lines classified as HER2-positive and basal-like.

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Section: Discussioncontrasting

confidence: 80%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

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Prognostic significance of hedgehog signaling network‐related gene expression in breast cancer patients

Kuehn

Espinoza-Sánchez

Teixeira

et al. 2021

J of Cellular Biochemistry

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“…These data suggest rapid alterations in plasticity and metastatic characteristics in response to signals that emanate from neighboring tumor cells, underscoring the critical nature of cell-cell crosstalk in inducing a plastic phenotype. Importantly, co-expression of GLI1 and two GLI1 targets, EGFR and Snail, are associated with worse outcome in breast cancer patients (Rudolph et al, 2018), further underscoring the clinical relevance of this pathway.…”

Section: The Hedgehog (Hh) Pathwaymentioning

confidence: 95%

Cellular Plasticity in Breast Cancer Progression and Therapy

Kong

Hughes

Ford

2020

Front. Mol. Biosci.

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With the exception of non-melanoma skin cancer, breast cancer is the most frequently diagnosed malignant disease among women, with the majority of mortality being attributable to metastatic disease. Thus, even with improved early screening and more targeted treatments which may enable better detection and control of early disease progression, metastatic disease remains a significant problem. While targeted therapies exist for breast cancer patients with particular subtypes of the disease (Her2+ and ER/PR+), even in these subtypes the therapies are often not efficacious once the patient's tumor metastasizes. Increases in stemness or epithelial-to-mesenchymal transition (EMT) in primary breast cancer cells lead to enhanced plasticity, enabling tumor progression, therapeutic resistance, and distant metastatic spread. Numerous signaling pathways, including MAPK, PI3K, STAT3, Wnt, Hedgehog, and Notch, amongst others, play a critical role in maintaining cell plasticity in breast cancer. Understanding the cellular and molecular mechanisms that regulate breast cancer cell plasticity is essential for understanding the biology of breast cancer progression and for developing novel and more effective therapeutic strategies for targeting metastatic disease. In this review we summarize relevant literature on mechanisms associated with breast cancer plasticity, tumor progression, and drug resistance.

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“…Combined targeting of the PI3K/AKT and Hh pathway might also be a rationale strategy to overcome resistance [40]. Our group also identified co-expression of GLI1 and two GLI1 targets, EGFR and SNAI1, to be associated with worse disease-free survival in HR breast cancer [42]. It is therefore important to develop biomarkers such as the GLI1 dependent gene expression signature to identify patients who are likely to respond to Hh directed therapy.…”

Section: Hedgehog Pathway In Hormone Receptor Positive Breast Cancermentioning

confidence: 99%

The Hedgehog Signaling Pathway: A Viable Target in Breast Cancer?

Bhateja

Cherian

Majumder

et al. 2019

Cancers

104

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The hedgehog (Hh) pathway plays a key role in embryonic development and stem cell programs. Deregulation of the Hh pathway is a key driver of basal cell carcinoma, and therapeutic targeting led to approval of Hh inhibitor, vismodegib, in the management of this cancer. The Hh pathway is implicated in other malignancies including hormone receptor (HR+) positive and triple negative breast cancer (TNBC). Hh signaling, which is activated in human mammary stem cells, results in activation of glioma-associated oncogene (GLI) transcription factors. High GLI1 expression correlates with worse outcomes in breast cancer. Non-canonical GLI1 activation is one mechanism by which estrogen exposure promotes breast cancer stem cell proliferation and epithelial–mesenchymal transition. Tamoxifen resistant cell lines show aberrant activation of Hh signaling, and knockdown of Hh pathway inhibited growth of tamoxifen resistant cells. As in other cancers Hh signaling is activated by the PI3K/AKT pathway in these endocrine resistant cell lines. Hh pathway activation has also been reported to mediate chemotherapy resistance in TNBC via various mechanisms including paracrine signaling to tumor micro-environment and selective proliferation of cancer stem cells. Co-activation of Hh and Wnt signaling pathways is a poor prognostic marker in TNBC. Early phase clinical trials are evaluating the combination of smoothened (SMO) inhibitors and chemotherapy in TNBC. In addition to SMO inhibitors like vismodegib and sonidegib, which are in clinical use for basal cell carcinoma, GLI1 inhibitors like GANT58 and GANT61 are in preclinical drug development and might be an effective mechanism to overcome drug resistance in breast cancer. Gene signatures predictive of Hh pathway activation could enrich for patients likely to respond to these agents.

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A hedgehog pathway-dependent gene signature is associated with poor clinical outcomes in Luminal A breast cancer

Abstract: We have identified a novel GLI1 gene signature that is associated with worse clinical outcomes among the patients with Luminal A subtype of breast cancer.

Cited by 7 publications

References 37 publications

Prognostic significance of hedgehog signaling network‐related gene expression in breast cancer patients

Prognostic significance of hedgehog signaling network‐related gene expression in breast cancer patients

Cellular Plasticity in Breast Cancer Progression and Therapy

The Hedgehog Signaling Pathway: A Viable Target in Breast Cancer?

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