Nuclear PDCD4 Expression Defines a Subset of Luminal B-Like Breast Cancers with Good Prognosis

Madera, Santiago; Chervo, María Florencia; Chiauzzi, Violeta A.; Pereyra, Matías G.; Venturutti, Leandro; Izzo, Franco; Deamicis, Agustina Roldán; Guzmán, Pablo; Dupont, Agustina; Roa, Juan Carlos; Cenciarini, Mauro E.; Barchuk, Sabrina; Figurelli, Silvina; Vecchia, Daniel Lopez Della; Levit, Claudio; Lebersztein, Gabriel; Anfuso, Fabiana; Castiglioni, Teresa; Cortese, E; Ares, Sandra; Deza, Ernesto Gil; Gercovich, Felipe G.; Proietti, Cecilia J.; Schillaci, Roxana; Russo, R; Elizalde, Patricia V.

doi:10.1007/s12672-020-00392-4

Cited by 8 publications

(9 citation statements)

References 73 publications

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“…T47D cells, from the luminal subtype, express estrogen and progesterone receptors (PR) and low levels of MErbB-2 (ref. [ 28 ]). BT-474 and murine C4HD cells mimic the estrogen receptor- and PR-positive, MErbB-2-overexpressing subtype [ 28 , 29 ].…”

Section: Resultsmentioning

confidence: 99%

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Halting ErbB-2 isoforms retrograde transport to the nucleus as a new theragnostic approach for triple-negative breast cancer

et al. 2022

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Triple-negative breast cancer (TNBC) is clinically defined by the absence of estrogen and progesterone receptors and the lack of membrane overexpression or gene amplification of receptor tyrosine kinase ErbB-2/HER2. Due to TNBC heterogeneity, clinical biomarkers and targeted therapies for this disease remain elusive. We demonstrated that ErbB-2 is localized in the nucleus (NErbB-2) of TNBC cells and primary tumors, from where it drives growth. We also discovered that TNBC expresses both wild-type ErbB-2 (WTErbB-2) and alternative ErbB-2 isoform c (ErbB-2c). Here, we revealed that the inhibitors of the retrograde transport Retro-2 and its cyclic derivative Retro-2.1 evict both WTErbB-2 and ErbB-2c from the nucleus of BC cells and tumors. Using BC cells from several molecular subtypes, as well as normal breast cells, we demonstrated that Retro-2 specifically blocks proliferation of BC cells expressing NErbB-2. Importantly, Retro-2 eviction of both ErbB-2 isoforms from the nucleus resulted in a striking growth abrogation in multiple TNBC preclinical models, including tumor explants and xenografts. Our mechanistic studies in TNBC cells revealed that Retro-2 induces a differential accumulation of WTErbB-2 at the early endosomes and the plasma membrane, and of ErbB-2c at the Golgi, shedding new light both on Retro-2 action on endogenous protein cargoes undergoing retrograde transport, and on the biology of ErbB-2 splicing variants. In addition, we revealed that the presence of a functional signal peptide and a nuclear export signal (NES), both located at the N-terminus of WTErbB-2, and absent in ErbB-2c, accounts for the differential subcellular distribution of ErbB-2 isoforms upon Retro-2 treatment. Our present discoveries provide evidence for the rational repurposing of Retro-2 as a novel therapeutic agent for TNBC.

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Section: Resultsmentioning

confidence: 99%

“…[ 28 ]). BT-474 and murine C4HD cells mimic the estrogen receptor- and PR-positive, MErbB-2-overexpressing subtype [ 28 , 29 ]. We and others reported that in these lines, both heregulin β1 (HRGβ1), an ErbBs ligand, and progestins induced NErbB-2 translocation, which stimulated proliferation [ 30 ].…”

Section: Resultsmentioning

confidence: 99%

Halting ErbB-2 isoforms retrograde transport to the nucleus as a new theragnostic approach for triple-negative breast cancer

et al. 2022

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“…Anyhow, grouping all the possible alterations in the genes involved in the serine metabolism stratifying patients between the altered and the unaltered group, there is a strong difference in terms of progression free survival with a better prognosis for the unaltered group (p < 0.001) (Fig. 4 G), this might be regarded as the development of a potential prediction algorithm as already done in many other clinical contexts [ 131 – 134 ].…”

Section: One-carbon and Serine Metabolism Impact On Prostate Cancer Progressionmentioning

confidence: 88%

Serine and one-carbon metabolisms bring new therapeutic venues in prostate cancer

et al. 2021

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Serine and one-carbon unit metabolisms are essential biochemical pathways implicated in fundamental cellular functions such as proliferation, biosynthesis of important anabolic precursors and in general for the availability of methyl groups. These two distinct but interacting pathways are now becoming crucial in cancer, the de novo cytosolic serine pathway and the mitochondrial one-carbon metabolism. Apart from their role in physiological conditions, such as epithelial proliferation, the serine metabolism alterations are associated to several highly neoplastic proliferative pathologies. Accordingly, prostate cancer shows a deep rearrangement of its metabolism, driven by the dependency from the androgenic stimulus. Several new experimental evidence describes the role of a few of the enzymes involved in the serine metabolism in prostate cancer pathogenesis. The aim of this study is to analyze gene and protein expression data publicly available from large cancer specimens dataset, in order to further dissect the potential role of the abovementioned metabolism in the complex reshaping of the anabolic environment in this kind of neoplasm. The data suggest a potential role as biomarkers as well as in cancer therapy for the genes (and enzymes) belonging to the one-carbon metabolism in the context of prostatic cancer.

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“…Moreover, expression levels of PDCD genes have been demonstrated to be altered in tumor samples and cancer cell lines ( 16 , 17 ). At present, there is no evidence demonstrating a conclusive link between members of PDCD gene family ( 4 ).…”

Section: Introductionmentioning

confidence: 99%

Interplay Between Non-Coding RNAs and Programmed Cell Death Proteins

et al. 2022

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Programmed cell death (PDCD) family of proteins includes at least 12 members, function of seven of them being more investigated. These members are PDCD1, PDCD2, PDCD4, PDCD5, PDCD6, PDCD7 and PDCD10. Consistent with the important roles of these proteins in the regulation of apoptosis, dysregulation of PDCDs is associated with diverse disorders ranging from intervertebral disc degeneration, amyotrophic lateral sclerosis, immune thrombocytopenia, type 1 diabetes, congenital hypothyroidism, Alzheimer’s disease to different types of cancers. More recently, the interaction between non-coding RNAs and different members of PDCD family is being discovered. In the current study, we described the functional interactions between PDCDs and two classes of non-coding RNAs, namely microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). miR-21 and miR-183 are two miRNAs whose interactions with PDCDs have been assessed in different contexts. The lncRNAs interaction with PDCDs is mainly assessed in the context of neoplasia indicating the role of MALAT1, MEG3, SNHG14 and LINC00473 in this process.

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Nuclear PDCD4 Expression Defines a Subset of Luminal B-Like Breast Cancers with Good Prognosis

Cited by 8 publications

References 73 publications

Halting ErbB-2 isoforms retrograde transport to the nucleus as a new theragnostic approach for triple-negative breast cancer

Halting ErbB-2 isoforms retrograde transport to the nucleus as a new theragnostic approach for triple-negative breast cancer

Serine and one-carbon metabolisms bring new therapeutic venues in prostate cancer

Interplay Between Non-Coding RNAs and Programmed Cell Death Proteins

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