scholarly journals miR-146 connects stem cell identity with metabolism and pharmacological resistance in breast cancer

2021 ◽  
Vol 220 (5) ◽  
Author(s):  
Chiara Tordonato ◽  
Matteo Jacopo Marzi ◽  
Giovanni Giangreco ◽  
Stefano Freddi ◽  
Paola Bonetti ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Subtype ◽  
Transcriptional Analysis ◽  
Quiescent State ◽  
Tumor Initiating Cells ◽  
Physiological Relevance ◽  
Basal Like Breast Cancer ◽  
Xenograft Tumor Growth

Although ectopic overexpression of miRNAs can influence mammary normal and cancer stem cells (SCs/CSCs), their physiological relevance remains uncertain. Here, we show that miR-146 is relevant for SC/CSC activity. MiR-146a/b expression is high in SCs/CSCs from human/mouse primary mammary tissues, correlates with the basal-like breast cancer subtype, which typically has a high CSC content, and specifically distinguishes cells with SC/CSC identity. Loss of miR-146 reduces SC/CSC self-renewal in vitro and compromises patient-derived xenograft tumor growth in vivo, decreasing the number of tumor-initiating cells, thus supporting its pro-oncogenic function. Transcriptional analysis in mammary SC-like cells revealed that miR-146 has pleiotropic effects, reducing adaptive response mechanisms and activating the exit from quiescent state, through a complex network of finely regulated miRNA targets related to quiescence, transcription, and one-carbon pool metabolism. Consistent with these findings, SCs/CSCs display innate resistance to anti-folate chemotherapies either in vitro or in vivo that can be reversed by miR-146 depletion, unmasking a “hidden vulnerability” exploitable for the development of anti-CSC therapies.

scholarly journals Isoform-specific promotion of breast cancer tumorigenicity by TBX3 involves induction of angiogenesis

2019 ◽  
Vol 100 (3) ◽  
pp. 400-413
Author(s):  
Milica Krstic ◽  
Haider M. Hassan ◽  
Bart Kolendowski ◽  
M. Nicole Hague ◽  
Pieter. H. Anborgh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Molecular Subtype ◽  
Xenograft Model ◽  
Tumor Formation ◽  
Transcriptional Analysis ◽  
Breast Cancer Cell Lines ◽  
Tumor Vascularity ◽  
Mouse Xenograft Model

Abstract TBX3 is a member of the highly conserved family of T-box transcription factors involved in embryogenesis, organogenesis and tumor progression. While the functional role of TBX3 in tumorigenesis has been widely studied, less is known about the specific functions of the different isoforms (TBX3iso1 and TBX3iso2) which differ in their DNA-binding domain. We therefore sought to investigate the functional consequence of this highly conserved splice event as it relates to TBX3-induced tumorigenesis. By utilizing a nude mouse xenograft model, we have identified differential tumorigenic potential between TBX3 isoforms, with TBX3iso1 overexpression more commonly associated with invasive carcinoma and high tumor vascularity. Transcriptional analysis of signaling pathways altered by TBX3iso1 and TBX3iso2 overexpression revealed significant differences in angiogenesis-related genes. Importantly, osteopontin (OPN), a cancer-associated secreted phosphoprotein, was significantly up-regulated with TBX3iso1 (but not TBX3iso2) overexpression. This pattern was observed across three non/weakly-tumorigenic breast cancer cell lines (21PT, 21NT, and MCF7). Up-regulation of OPN in TBX3iso1 overexpressing cells was associated with induction of hyaluronan synthase 2 (HAS2) expression and increased retention of hyaluronan in pericellular matrices. These transcriptional changes were accompanied by the ability to induce endothelial cell vascular channel formation by conditioned media in vitro, which could be inhibited through addition of an OPN neutralizing antibody. Within the TCGA breast cancer cohort, we identified an 8.1-fold higher TBX3iso1 to TBX3iso2 transcript ratio in tumors relative to control, and this ratio was positively associated with high-tumor grade and an aggressive molecular subtype. Collectively, the described changes involving TBX3iso1-dependent promotion of angiogenesis may thus serve as an adaptive mechanism within breast cancer cells, potentially explaining differences in tumor formation rates between TBX3 isoforms in vivo. This study is the first of its kind to report significant functional differences between the two TBX3 isoforms, both in vitro and in vivo.

In vitro and in vivo studies of gold(I) azolate/phosphane complexes for the treatment of basal like breast cancer

2018 ◽  
Vol 155 ◽  
pp. 418-427 ◽  
Author(s):  
Valentina Gambini ◽  
Martina Tilio ◽  
Eunice Wairimu Maina ◽  
Cristina Andreani ◽  
Caterina Bartolacci ◽  
...  
Keyword(s):  
Breast Cancer ◽  
In Vivo Studies ◽  
Basal Like Breast Cancer

scholarly journals In vitro and in vivo analysis of B-Myb in basal-like breast cancer

Oncogene ◽  
2008 ◽  
Vol 28 (5) ◽  
pp. 742-751 ◽  
Author(s):  
A R Thorner ◽  
K A Hoadley ◽  
J S Parker ◽  
S Winkel ◽  
R C Millikan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Basal Like Breast Cancer ◽  
In Vivo Analysis

scholarly journals The Histone Demethylase LSD1/ΚDM1A Mediates Chemoresistance in Breast Cancer via Regulation of a Stem Cell Program

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1585 ◽  
Author(s):  
John Verigos ◽  
Panagiotis Karakaidos ◽  
Dimitris Kordias ◽  
Alexandra Papoudou-Bai ◽  
Zoi Evangelou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Tumor Cells ◽  
Histone Demethylase ◽  
Small Subset ◽  
Tumor Initiating Cells ◽  
Female Population ◽  
Number Of Patients

Breast cancer is the leading cause of cancer death in the female population, despite advances in diagnosis and treatment. The highly heterogeneous nature of the disease represents a major obstacle to successful therapy and results in a significant number of patients developing drug resistance and, eventually, suffering from tumor relapse. Cancer stem cells (CSCs) are a small subset of tumor cells characterized by self-renewal, increased tumor-initiation capacity, and resistance to conventional therapies. As such, they have been implicated in the etiology of tumor recurrence and have emerged as promising targets for the development of novel therapies. Here, we show that the histone demethylase lysine-specific demethylase 1 (LSD1) plays an important role in the chemoresistance of breast cancer cells. Our data, from a series of in vitro and in vivo assays, advocate for LSD1 being critical in maintaining a pool of tumor-initiating cells that may contribute to the development of drug resistance. Combinatory administration of LSD1 inhibitors and anti-cancer drugs is more efficacious than monotherapy alone in eliminating all tumor cells in a 3D spheroid system. In conclusion, we provide compelling evidence that LSD1 is a key regulator of breast cancer stemness and a potential target for the design of future combination therapies.

scholarly journals Targeting PML in triple negative breast cancer elicits growth suppression and senescence

2019 ◽  
Vol 27 (4) ◽  
pp. 1186-1199 ◽  
Author(s):  
Leire Arreal ◽  
Marco Piva ◽  
Sonia Fernández ◽  
Ajinkya Revandkar ◽  
Ariane Schaub- Clerigué ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cell Function ◽  
Breast Cancer Subtype ◽  
Growth Arrest ◽  
Promoter Regions

Abstract Oncogene addiction postulates that the survival and growth of certain tumor cells is dependent upon the activity of one oncogene, despite their multiple genetic and epigenetic abnormalities. This phenomenon provides a foundation for molecular targeted therapy and a rationale for oncogene-based stratification. We have previously reported that the Promyelocytic Leukemia protein (PML) is upregulated in triple negative breast cancer (TNBC) and it regulates cancer-initiating cell function, thus suggesting that this protein can be therapeutically targeted in combination with PML-based stratification. However, the effects of PML perturbation on the bulk of tumor cells remained poorly understood. Here we demonstrate that TNBC cells are addicted to the expression of this nuclear protein. PML inhibition led to a remarkable growth arrest combined with features of senescence in vitro and in vivo. Mechanistically, the growth arrest and senescence were associated to a decrease in MYC and PIM1 kinase levels, with the subsequent accumulation of CDKN1B (p27), a trigger of senescence. In line with this notion, we found that PML is associated to the promoter regions of MYC and PIM1, consistent with their direct correlation in breast cancer specimens. Altogether, our results provide a feasible explanation for the functional similarities of MYC, PIM1, and PML in TNBC and encourage further study of PML targeting strategies for the treatment of this breast cancer subtype.

scholarly journals Global transcriptional analysis identifies a novel role for SOX4 in tumor-induced angiogenesis

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Stephin J Vervoort ◽  
Olivier G de Jong ◽  
M Guy Roukens ◽  
Cynthia L Frederiks ◽  
Jeroen F Vermeulen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Transcription Factor ◽  
Poor Prognosis ◽  
Target Gene ◽  
Gene Selection ◽  
Mammary Tumorigenesis ◽  
Breast Tumors ◽  
Transcriptional Analysis

The expression of the transcription factor SOX4 is increased in many human cancers, however, the pro-oncogenic capacity of SOX4 can vary greatly depending on the type of tumor. Both the contextual nature and the mechanisms underlying the pro-oncogenic SOX4 response remain unexplored. Here, we demonstrate that in mammary tumorigenesis, the SOX4 transcriptional network is dictated by the epigenome and is enriched for pro-angiogenic processes. We show that SOX4 directly regulates endothelin-1 (ET-1) expression and can thereby promote tumor-induced angiogenesis both in vitro and in vivo. Furthermore, in breast tumors, SOX4 expression correlates with blood vessel density and size, and predicts poor-prognosis in patients with breast cancer. Our data provide novel mechanistic insights into context-dependent SOX4 target gene selection, and uncover a novel pro-oncogenic role for this transcription factor in promoting tumor-induced angiogenesis. These findings establish a key role for SOX4 in promoting metastasis through exploiting diverse pro-tumorigenic pathways.

scholarly journals Tumor Suppressor PLK2 May Serve as a Biomarker in Triple-Negative Breast Cancer for Improved Response to PLK1 Therapeutics

2021 ◽  
Vol 1 (3) ◽  
pp. 178-193
Author(s):  
Yang Gao ◽  
Elena B. Kabotyanski ◽  
Jonathan H. Shepherd ◽  
Elizabeth Villegas ◽  
Deanna Acosta ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Null Mouse ◽  
Chromosome 5Q ◽  
Basal Like Breast Cancer ◽  
Cycle Regulation

Polo-like kinase (PLK) family members play important roles in cell-cycle regulation. The founding member PLK1 is oncogenic and preclinically validated as a cancer therapeutic target. Paradoxically, frequent loss of chromosome 5q11–35, which includes PLK2, is observed in basal-like breast cancer. In this study, we found that PLK2 was tumor suppressive in breast cancer, preferentially in basal-like and triple-negative breast cancer (TNBC) subtypes. Knockdown of PLK1 rescued phenotypes induced by PLK2 loss both in vitro and in vivo. We also demonstrated that PLK2 directly interacted with PLK1 at prometaphase through the kinase but not the polo-box domains of PLK2, suggesting PLK2 functioned at least partially through the interaction with PLK1. Furthermore, an improved treatment response was seen in both Plk2-deleted/low mouse preclinical and patient-derived xenograft (PDX) TNBC models using the PLK1 inhibitor volasertib alone or in combination with carboplatin. Reexpression of PLK2 in an inducible PLK2-null mouse model reduced the therapeutic efficacy of volasertib. In summary, this study delineates the effects of chromosome 5q loss in TNBC that includes PLK2, the relationship between PLK2 and PLK1, and how this may render PLK2-deleted/low tumors more sensitive to PLK1 inhibition in combination with chemotherapy. Significance: The tumor-suppressive role of PLK2, and its relationship with oncogene PLK1, provide a mechanistic rationalization to use PLK1 inhibitors in combination with chemotherapy to treat PLK2-low/deleted tumors. TNBC, and other cancers with low PLK2 expression, are such candidates to leverage precision medicine to identify patients who might benefit from treatment with these inhibitors.

Precise discrimination of Luminal A breast cancer subtype using an aptamer in vitro and in vivo

Nanoscale ◽  
2020 ◽  
Vol 12 (38) ◽  
pp. 19689-19701 ◽  
Author(s):  
Mei Liu ◽  
Biao Zhang ◽  
Zhiyang Li ◽  
Zhifei Wang ◽  
Song Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Subtype ◽  
Dna Aptamer ◽  
Luminal A ◽  
Cancer Subtype

A truncated DNA aptamer for precise discrimination of Luminal A breast cancer subtype was developed.

scholarly journals MELK is an oncogenic kinase essential for mitotic progression in basal-like breast cancer cells

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Yubao Wang ◽  
Young-Mi Lee ◽  
Lukas Baitsch ◽  
Alan Huang ◽  
Yi Xiang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Progesterone Receptors ◽  
Luminal Breast Cancer ◽  
Mouse Development ◽  
Basal Like Breast Cancer ◽  
Aggressive Subtype

Despite marked advances in breast cancer therapy, basal-like breast cancer (BBC), an aggressive subtype of breast cancer usually lacking estrogen and progesterone receptors, remains difficult to treat. In this study, we report the identification of MELK as a novel oncogenic kinase from an in vivo tumorigenesis screen using a kinome-wide open reading frames (ORFs) library. Analysis of clinical data reveals a high level of MELK overexpression in BBC, a feature that is largely dependent on FoxM1, a master mitotic transcription factor that is also found to be highly overexpressed in BBC. Ablation of MELK selectively impairs proliferation of basal-like, but not luminal breast cancer cells both in vitro and in vivo. Mechanistically, depletion of MELK in BBC cells induces caspase-dependent cell death, preceded by defective mitosis. Finally, we find that Melk is not required for mouse development and physiology. Together, these data indicate that MELK is a normally non-essential kinase, but is critical for BBC and thus represents a promising selective therapeutic target for the most aggressive subtype of breast cancer.

Sign in / Sign up

Export Citation Format

Share Document