Basal/HER2 breast carcinomas

Martín-Castillo, Begoña; Oliveras‐Ferraros, Cristina; Vázquez-Martín, Alejandro; Cufí, Sílvia; Moreno, José Manuel; Corominas-Faja, Bruna; Urruticoechea, Ander; Martín, Ángel G.; López-Bonet, Eugeni; Menendez, Javier A.

doi:10.4161/cc.23274

Cited by 47 publications

(37 citation statements)

References 172 publications

(175 reference statements)

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“…2, both luminal progenitor and basal myoepithelial stem cells contribute to mammary tumor development in MMTV-Neu-Tg mice. However, previous studies have shown that the luminal progenitors are the origin of MMTV-Neu-Tg driven mammary tumor (23) and that basal stem cells are increased during later stages of the mammary tumor development, which contributes to drug resistance and metastasis (24, 25). Further, we have shown that DNMTs, especially DNMT1, play a critical role in regulation of luminal progenitor and basal myoepithelial stem cells and that functional inactivation of DNMT1 significantly reduces both of these populations (10).…”

Section: Resultsmentioning

confidence: 99%

Combined Inhibition of DNMT and HDAC Blocks the Tumorigenicity of Cancer Stem-like Cells and Attenuates Mammary Tumor Growth

et al. 2016

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Recently, impressive technical advancements have been made in the isolation and validation of mammary stem cells and cancer stem cells (CSCs), but the signaling pathways that regulate stem cell self-renewal are largely unknown. Further, CSCs are believed to contribute to chemo- and radioresistance. In this study, we used the MMTV-Neu-Tg mouse mammary tumor model to identify potential new strategies for eliminating CSCs. We found that both luminal progenitor and basal stem cells are susceptible to genetic and epigenetic modifications, which facilitate oncogenic transformation and tumorigenic potential. A combination of the DNMT inhibitor 5-azacytidine and the HDAC inhibitor butyrate markedly reduced CSC abundance and increased the overall survival in this mouse model. RNA-seq analysis of CSCs treated with 5-azacytidine plus butyrate provided evidence that inhibition of chromatin modifiers blocks growth-promoting signaling molecules such as RAD51AP1 and SPC25, which play key roles in DNA damage repair and kinetochore assembly. Moreover, RAD51AP1 and SPC25 were significantly overexpressed in human breast tumor tissues and were associated with reduced overall patient survival. In conclusion, our studies suggest that breast CSCs are intrinsically sensitive to genetic and epigenetic modifications and can therefore be significantly affected by epigenetic-based therapies, warranting further investigation of combined DNMT and HDAC inhibition in refractory or drug-resistant breast cancer.

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Section: Resultsmentioning

confidence: 99%

Combined Inhibition of DNMT and HDAC Blocks the Tumorigenicity of Cancer Stem-like Cells and Attenuates Mammary Tumor Growth

et al. 2016

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“…That metformin could not entirely restore the abundance of H3K27me3 occurring in the liver of HFD‐fed animals (Vella et al., 2013) might reflect the epigenetic incapacity of HFD‐damaged tissues to fully benefit from the expected response to metformin unless combined with diet reversal (Riera‐Borrull et al., 2017). At a dose of 250 mg kg −1 day −1 i.p., a route of administration that is equivalent to 1,200 mg/day metformin for a 60 kg individual (Reagan‐Shaw, Nihal & Ahmad, 2008) and yields plasma concentrations in the low micromolar range (Chandel et al., 2016; Dowling et al., 2016; Memmott et al., 2010; Menendez, Martin‐Castillo & Joven, 2016), metformin treatment resulted in a significant twofold reduction in the tumor volume in xenograft‐bearing mice highly enriched with tumor‐initiating cancer stem cells (CSC) (Cufi et al., 2012; Martin‐Castillo et al., 2013; Oliveras‐Ferraros et al., 2012) that was accompanied by a noteworthy twofold augmentation of global H3K27me3 in tumor tissues. Because decreased abundance of H3K27me3 is a predictor of cancer aggressiveness independently of the expression of the H3K27me3 methyltransferase EZH2 (Holm et al., 2012; Wei et al., 2008) closely related to the maintenance of poorly differentiated CSC (Sakaki et al., 2015; Yan et al., 2017), our findings suggest that metformin might exert a suppressive influence on the CSC phenotype by enhancing deposition of the repressive H3K27me3 mark.…”

Section: Discussionmentioning

confidence: 99%

Metformin directly targets the H3K27me3 demethylase KDM6A/UTX

et al. 2018

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SummaryMetformin, the first drug chosen to be tested in a clinical trial aimed to target the biology of aging per se, has been clinically exploited for decades in the absence of a complete understanding of its therapeutic targets or chemical determinants. We here outline a systematic chemoinformatics approach to computationally predict biomolecular targets of metformin. Using several structure‐ and ligand‐based software tools and reference databases containing 1,300,000 chemical compounds and more than 9,000 binding sites protein cavities, we identified 41 putative metformin targets including several epigenetic modifiers such as the member of the H3K27me3‐specific demethylase subfamily, KDM6A/UTX. AlphaScreen and AlphaLISA assays confirmed the ability of metformin to inhibit the demethylation activity of purified KDM6A/UTX enzyme. Structural studies revealed that metformin might occupy the same set of residues involved in H3K27me3 binding and demethylation within the catalytic pocket of KDM6A/UTX. Millimolar metformin augmented global levels of H3K27me3 in cultured cells, including reversion of global loss of H3K27me3 occurring in premature aging syndromes, irrespective of mitochondrial complex I or AMPK. Pharmacological doses of metformin in drinking water or intraperitoneal injection significantly elevated the global levels of H3K27me3 in the hepatic tissue of low‐density lipoprotein receptor‐deficient mice and in the tumor tissues of highly aggressive breast cancer xenograft‐bearing mice. Moreover, nondiabetic breast cancer patients receiving oral metformin in addition to standard therapy presented an elevated level of circulating H3K27me3. Our biocomputational approach coupled to experimental validation reveals that metformin might directly regulate the biological machinery of aging by targeting core chromatin modifiers of the epigenome.

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“…In preclinical models, we demonstrated that PTEN knockdown in HER2-positive breast cancer cells generates trastuzumab resistant CSCs through activation of an inflammatory loop mediated by NF-κB and IL-6 (27). It has been proposed that the trastuzumab resistance in HER2+ER− (basal) compared to HER2+ER+ (luminal) breast tumors may relate to CSC regulatory pathways (28). In addition, recent studies have demonstrated that HER2 activating mutations may contribute to trastuzumab resistance (29).…”

Section: Interaction Of Her2 and Other Signaling Pathways In The Regumentioning

confidence: 99%

HER2 and Breast Cancer Stem Cells: More than Meets the Eye

2013

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The development of HER2-targeting agents has dramatically altered the natural history of HER2-positive breast cancer and is often cited as a prime example of the effectiveness of molecularly targeted therapy. Emerging data suggests that the remarkable clinical efficacy of these agents may be related to their ability to target the breast cancer stem cell (BCSC) population. A new study suggests that the regulation of BCSC by HER2 may extend to breast cancers that do not display HER2 gene amplification. In these tumors, HER2 is selectively expressed in the CSC population and this expression is regulated by the tumor microenvironment. In mouse models, trastuzumab blocked growth of these “HER2-negative” tumors when administered in the adjuvant setting but had no effect on established tumors. These studies provide a potential biological explanation for retrospective analysis of clinical trials which surprisingly suggest that the clinical benefits of adjuvant trastuzumab may extend to women currently classified as “HER2-negative. In addition to having significant implications for breast cancer therapy, these studies suggest the need to reevaluate the role of HER2 in regulating CSCs in other tumor types. Furthermore, these studies suggest that effective adjuvant therapies may need to target the CSC population.

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Basal/HER2 breast carcinomas

Cited by 47 publications

References 172 publications

Combined Inhibition of DNMT and HDAC Blocks the Tumorigenicity of Cancer Stem-like Cells and Attenuates Mammary Tumor Growth

Combined Inhibition of DNMT and HDAC Blocks the Tumorigenicity of Cancer Stem-like Cells and Attenuates Mammary Tumor Growth

Metformin directly targets the H3K27me3 demethylase KDM6A/UTX

HER2 and Breast Cancer Stem Cells: More than Meets the Eye

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