Loss of STAT6 leads to anchorage-independent growth and trastuzumab resistance in HER2+ breast cancer cells

DiScala, Molly; Najor, Matthew S.; Yung, Timothy; Morgan, Deri; Abukhdeir, Abde M.; Cobleigh, Melody A.

doi:10.1371/journal.pone.0234146

Cited by 7 publications

(3 citation statements)

References 29 publications

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“…Here, and in keeping with reported functions for SOCS proteins as suppressors of JAK/STAT pathways, we did find that SOCS5 (and LINC01119) inhibited the phosphoactivation of STAT6, but not the traditional targets STAT1 or STAT3. Of pertinence, STAT6 has been described to act as a tumor suppressor in breast cancer 69,70 , providing a possible mechanism-of-action of LINC01119/SOCS5 in driving TNBC cell growth by curtailing STAT6 activation. In support of this notion are genetic data demonstrating STAT6 negative correlation with both LINC01119 and SOCS5 in patient cohorts, and the fact that STAT6 downregulation was itself associated with TNBC and forecasted poor TNBC patient prognosis (Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

The LINC01119-SOCS5 axis as a critical theranostic in triple-negative breast cancer

Schmoellerl

Mariani

et al. 2021

npj Breast Cancer

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The development of triple-negative breast cancer (TNBC) is critically regulated by certain tumor-microenvironment-associated cells called mesenchymal stem/stromal cells (MSCs), which we and others have shown promote TNBC progression by activating pro-malignant signaling in neighboring cancer cells. Characterization of these cascades would better our understanding of TNBC biology and bring about therapeutics that eliminate the morbidity and mortality associated with advanced disease. Here, we focused on the emerging class of RNAs called long non-coding RNAs or lncRNAs and utilized a MSC-supported TNBC progression model to identify specific family members of functional relevance to TNBC pathogenesis. Indeed, although some have been described to play functional roles in TNBC, activities of lncRNAs as mediators of tumor-microenvironment-driven TNBC development remain to be fully explored. We report that MSCs stimulate robust expression of LINC01119 in TNBC cells, which in turn induces suppressor of cytokine signaling 5 (SOCS5), leading to accelerated cancer cell growth and tumorigenesis. We show that LINC01119 and SOCS5 exhibit tight correlation across multiple breast cancer gene sets and that they are highly enriched in TNBC patient cohorts. Importantly, we present evidence that the LINC01119-SOCS5 axis represents a powerful prognostic indicator of adverse outcomes in TNBC patients, and demonstrate that its repression severely impairs cancer cell growth. Altogether, our findings identify LINC01119 as a major driver of TNBC development and delineate critical non-coding RNA theranostics of potential translational utility in the management of advanced TNBC, a class of tumors in most need of effective and targeted therapy.

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Section: Discussionmentioning

confidence: 99%

The LINC01119-SOCS5 axis as a critical theranostic in triple-negative breast cancer

Schmoellerl

Mariani

et al. 2021

npj Breast Cancer

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“…STAT6 acts as an important TF that takes part in the cell cycle, cell growth, and apoptosis. DiScala et al (2020 ) found that loss of STAT6 results in trastuzumab resistance in HER2+ breast cancer cells. IRF1 functions in immune response, DNA damage, and DNA repair.…”

Section: Discussionmentioning

confidence: 99%

Identification of the Prognostic Value Among Suppressor Of Cytokine Signaling Family Members in Kidney Renal Clear Cell Carcinoma

Zhang

Fang

et al. 2021

Front. Mol. Biosci.

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Background: Kidney renal clear cell carcinoma (KIRC) has become one of the most prevalent malignancies worldwide and remains a crucial cause of cancer-related morbidity and mortality. Aberrant activation of the JAK/STAT pathway acts as an important role in KIRC. The suppressor of cytokine signaling (SOCS) family members are the key negative regulators of the JAK/STAT pathway. SOCS family members have been verified to act as significant roles in regulating cellular responses to many cytokines and growth factors. However, whether the expression levels of SOCS affect the prognosis of patients with KIRC is still elusive.Methods: We first evaluated the expression of SOCS family genes in KIRC and determined the correlation between SOCS expression and different clinicopathological features. Then, we analyzed the genetic alterations, potential functions, transcription factor targets, and immune infiltration of SOCS family members based on the information available on public databases. Finally, we assessed the prognostic value of differentially expressed SOCS family members.Results: The expression levels of SOCS2, SOCS4, SOCS6, SOCS7, and CISH were downregulated in KIRC, and all SOCS genes were associated with clinicopathological features of patients with KIRC. SOCS family members have been predominantly related to protein binding, signaling adaptor activity, and JAK/STAT cascade. We found that STAT3, STAT6, and IRF1 are the key transcription factors that may be participated in the regulation of SOCS. We also found an association between the expression levels of SOCS and the immune infiltrates of KIRC. Finally, we have illuminated that SOCS1 and SOCS3 are risky genes, whereas SOCS2, SOCS4, SOCS6, SOCS7, and CISH are some of the protective genes for patients with KIRC; based on these, we have created a KIRC prognostic index for predicting the prognosis of patients of KIRC.Conclusion: Our study may contribute to further understanding the functions of SOCS genes in KIRC, which may help clinicians in selecting the appropriate drugs and predicting the outcomes for patients with KIRC.

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“…To investigate the relationship between HER2 overexpression and sensitivity to PARPi, we used lentivirus-mediate HER2 overexpression to create an isogenic panel of MCF-10A human breast epithelial cells, referred to as MCF-10A-HER2. Isogenic MCF-10A-HER2 cell lines were generated as previously described [22]. The resulting clones, exhibited EGFindependent growth, a surrogate marker of cell transformation in MCF-10A cells, indicating that cell growth is driven through HER2 receptor signaling [23].…”

Section: Her2 Overexpressing Mcf10a Cells Are Sensitive To Olaparibmentioning

confidence: 99%

Resistance to HER2-Targeted Therapies Results in Upregulation of MCL-1 and Sensitivity to Olaparib

Armstrong¹,

Najor²,

Rempert³

et al. 2020

ijSciences

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Loss of STAT6 leads to anchorage-independent growth and trastuzumab resistance in HER2+ breast cancer cells

Cited by 7 publications

References 29 publications

The LINC01119-SOCS5 axis as a critical theranostic in triple-negative breast cancer

The LINC01119-SOCS5 axis as a critical theranostic in triple-negative breast cancer

Identification of the Prognostic Value Among Suppressor Of Cytokine Signaling Family Members in Kidney Renal Clear Cell Carcinoma

Resistance to HER2-Targeted Therapies Results in Upregulation of MCL-1 and Sensitivity to Olaparib

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