Reprogramming of non-genomic estrogen signaling by the stemness factor SOX2 enhances the tumor-initiating capacity of breast cancer cells

Vázquez-Martín, Alejandro; Cufí, Sílvia; López-Bonet, Eugeni; Corominas-Faja, Bruna; Cuyàs, Elisabet; Vellón, Luciano; Iglesias, Juan Manuel; Leis, Olatz; Martín, Ángel G.; Menendez, Javier A.

doi:10.4161/cc.26692

Cited by 40 publications

(45 citation statements)

References 23 publications

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“…While tumor initiating capability is a classic hallmark of non-neoplastic cells displaying pluripotency, either as a natural feature or induced by genetic reprogramming [2,3], in cancer cells, abnormal expression of genes regulating developmental processes enhances their tumorigenicity [4][5][6].…”

Section: Introductionmentioning

confidence: 99%

Embryonic Stem Cell-Related Protein L1TD1 Is Required for Cell Viability, Neurosphere Formation, and Chemoresistance in Medulloblastoma

Santos

Silva

Rodini

et al. 2015

Stem Cells and Development

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Misexpression of stem cell-related genes may occur in some cancer cells, influencing patient's prognosis. This is the case of medulloblastoma, a common and clinically challenging malignant tumor of the central nervous system, where expression of the pluripotency factor, OCT4, is correlated with poor survival. A downstream target of OCT4, L1TD1 (LINE-1 type transposase domain-containing protein 1 family member), encodes a novel embryonic stem cell (ESC)-related protein involved in pluripotency and self-renewal of ESCs. L1TD1 is still poorly characterized and its expression pattern and function in cancer cells are virtually unknown. Although normally restricted to non-neoplastic undifferentiated cells and germ cells, we found that high L1TD1 expression also occurs in medulloblastoma cells, reaching levels similar to those found in ESCs, and is correlated with poor prognosis. Conversely to what is reported during normal cell differentiation, when differentiated cells remain healthy, despite L1TD1 downregulation, depletion of L1TD1 protein levels by targeted gene silencing significantly reduced medulloblastoma cell viability, inhibiting cell proliferation and inducing apoptosis. More strikingly, L1TD1 depletion downregulated expression of the neural stem cell markers, CD133 and Nestin, inhibited neurosphere generation capability, and sensitized medulloblastoma cells to temozolomide and cisplatin, two chemotherapeutic agents of clinical relevance in medulloblastoma treatment. Our findings provide insights about the contribution of pluripotency-related genes to a more aggressive tumor phenotype through their involvement in the acquisition of stem-like properties by cancer cells and point out L1TD1 as a potential therapeutic target in malignant brain tumors.

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Section: Introductionmentioning

confidence: 99%

Embryonic Stem Cell-Related Protein L1TD1 Is Required for Cell Viability, Neurosphere Formation, and Chemoresistance in Medulloblastoma

Santos

Silva

Rodini

et al. 2015

Stem Cells and Development

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show abstract

“…[2][3][4][5][6][7][8][9][10][11] Nonetheless, the striking similarity of the molecular features shared between iPS cell generation and tumorigenesis is providing key mechanistic insights on how CSC could actually arise, in some cases, from differentiated cells through a process of "pathological nuclear reprogramming." [12][13][14][15][16][17][18][19][20][21] A proof-of-concept demonstration of the close association between acquisition of stem cell properties by induced pluripotency and CSC-driven tumorigenesis has been recently carried out in a landmark study, showing that transient in vivo expression of reprogramming factors generates tumors with altered epigenetic states which cause abnormal growth of incompletely reprogrammed cells. 22 Though these findings are the first to confirm that premature termination of induced pluripotency can result in cancer development, it should be noted that oncogenic-transformed cells and iPS cells generated from common parental fibroblasts have been found to represent highly related, yet distinct, cell types based on expression profiling,share common "cellular ancestors" that develop along an equivalent molecular pathway(s) before they diverge.…”

Section: Metabolic Control Of Cancer Cell Stemness: Lessons From Ips mentioning

confidence: 99%

Metabolic control of cancer cell stemness: Lessons from iPS cells

Menendez

2015

Cell Cycle

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“…Additionally, crosstalk between ER and the nuclear factor κ-light-chain-enhancer of activated B cells pathway contributes to the upregulation of PHLDA1, directly through the increased transcription and indirectly through the inhibition of miR-181a/b (30). Estrogen (E2) was identified to enhance breast tumor-initiating cell survival by downregulating miR-140, which targets SOX2 (31). Concomitantly, the transcription of miR-140 was also inhibited by estrogen receptor α (ERα), which binds to the promoter of miR-140; reduced miR-140 increases breast tumor-initiating cell renewal via targeting SOX2 (32).…”

Section: Mirnas Regulate Bcsc Self-renewalmentioning

confidence: 99%

MicroRNAs, a subpopulation of regulators, are involved in breast cancer progression through regulating breast cancer stem cells (Review)

Fan

Chen

et al. 2017

Oncol Lett

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Abstract. Cancer stem cells (CSCs; also known as tumor-initiating cells) are essential effectors of tumor progression due to their self-renewal capacity, differentiation potential, tumorigenic ability and resistance to chemotherapy, all of which contribute to cancer relapse, metastasis and a poor prognosis. Breast cancer stem cells (BCSCs) have been identified to be involved in the processes of BC initiation, growth and recurrence. MicroRNAs (miRNAs) are a class of non-coding small RNAs of 19-23 nucleotides in length that regulate gene expression at the post-transcriptional level through various mechanisms, and serve critical roles in cancer progression. miRNAs have been demonstrated to elicit effects on BCSCs characteristics via the targeting of oncogenes or tumor suppressor genes. The present study focused on the effect of miRNAs on BCSC, including BCSC formation, self-renewal and differentiation, by which miRNAs may inhibit BCSC invasion and metastasis, modulate clonogenicity and tumorigenicity of BCSCs as well as regulate chemotherapy resistance to BC. Through an improved understanding of the association between BCSCs and miRNAs, a novel and safer therapeutic target for BC may be identified.

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Reprogramming of non-genomic estrogen signaling by the stemness factor SOX2 enhances the tumor-initiating capacity of breast cancer cells

Cited by 40 publications

References 23 publications

Embryonic Stem Cell-Related Protein L1TD1 Is Required for Cell Viability, Neurosphere Formation, and Chemoresistance in Medulloblastoma

Embryonic Stem Cell-Related Protein L1TD1 Is Required for Cell Viability, Neurosphere Formation, and Chemoresistance in Medulloblastoma

Metabolic control of cancer cell stemness: Lessons from iPS cells

MicroRNAs, a subpopulation of regulators, are involved in breast cancer progression through regulating breast cancer stem cells (Review)

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