RETRACTED ARTICLE: Progesterone receptor assembly of a transcriptional complex along with activator protein 1, signal transducer and activator of transcription 3 and ErbB-2 governs breast cancer growth and predicts response to endocrine therapy

Flaqué, María Celeste Díaz; Galigniana, Natalia M.; Béguelin, Wendy; Vicario, Rocío; Proietti, Cecilia J.; Russo, R; Rivas, Martín A.; Tkach, Mercedes; Guzmán, Pablo; Roa, Juan Carlos; Maronna, Esteban; Pineda, Viviana; Muñoz, Sergio; Mercogliano, María F.; Charreau, Eduardo H.; Yankilevich, Patricio; Schillaci, Roxana; Elizalde, Patricia V.

doi:10.1186/bcr3587

Cited by 31 publications

(27 citation statements)

References 76 publications

(156 reference statements)

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“…Numerous findings strongly demonstrated that fulllength ErbB-2 is present in the nucleus of BC cells, where it binds promoters/enhancers of target genes to regulate biological responses in BC (Tan et al 2002, Wang et al 2004, Kim et al 2009, Beguelin et al 2010, Li et al 2011, Diaz Flaque et al 2013a,b, Cordo Russo et al 2015. Importantly, the development of more sophisticated techniques to study protein trafficking from the cytoplasmic membrane to different subcellular compartments, allowed further understanding of the mechanism involved in ErbB-2 nuclear translocation.…”

Section: Nuclear Erbb-2 Action In Breast Cancermentioning

confidence: 99%

“…Also, providing consistent correlation between ErbB-2's role as a coactivator and its ability to promote BC growth, another study demonstrated that progestins induce the assembly of a transcriptional complex among activator protein 1 (AP-1), Stat3, PR and ErbB-2 at a region of the cyclin D1 promoter containing both AP-1 response elements (TRE) and GAS sites (Diaz Flaque et al 2013a). This array of transcription factors (AP-1 and Stat3) whose response elements are clustered in the DNA, plus their interacting cofactors (PR and ErbB-2) and coactivators (P300 and CBP), function cooperatively to induce cyclin D1 promoter activation as well as in vitro and in vivo BC growth driven by progestins (Diaz Flaque et al 2013a).…”

Section: :12mentioning

confidence: 99%

“…We have come a long way since the days when the notion of ErbBs in the nucleus was so utterly challenging that it was regarded as either 'ridiculous or sublime' (Waugh & Hsuan 2001). Indeed, compelling evidence has shown ErbB-2 localization in the nucleus of BC cells, where it functions as a transcriptional regulator (Tan et al 2002, Wang et al 2004, Kim et al 2009, Beguelin et al 2010, Li et al 2011, Diaz Flaque et al 2013a,b, Cordo Russo et al 2015. However, the role of nuclear ErbB-2 (NErbB-2) as a biomarker and a target of therapy in BC is still unexplored.…”

Section: Introductionmentioning

confidence: 99%

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ErbB-2 nuclear function in breast cancer growth, metastasis and resistance to therapy

Elizalde¹,

Russo²,

Chervo³

et al. 2016

Endocrine-Related Cancer

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Approximately 15-20% of breast cancers (BC) show either membrane overexpression of ErbB-2 (MErbB-2), a member of the ErbBs family of receptor tyrosine kinases, or ERBB2 gene amplification. Until the development of MErbB-2-targeted therapies, this BC subtype, called ErbB-2-positive, was associated with increased metastatic potential and poor prognosis. Although these therapies have significantly improved overall survival and cure rates, resistance to available drugs is still a major clinical issue. In its classical mechanism, MErbB-2 activates downstream signaling cascades, which transduce its effects in BC. The fact that ErbB-2 is also present in the nucleus of BC cells was discovered over twenty years ago. Also, compelling evidence revealed a non-canonical function of nuclear ErbB-2 as a transcriptional regulator. As a deeper understanding of nuclear ErbB-2 actions would be crucial to the disclosure of its role as a biomarker and a target of therapy in BC, we will here review its function in BC, in particular, its role in growth, metastatic spreading and response to currently available MErbB-2-positive BC therapies.

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Section: Nuclear Erbb-2 Action In Breast Cancermentioning

confidence: 99%

Section: :12mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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ErbB-2 nuclear function in breast cancer growth, metastasis and resistance to therapy

Elizalde¹,

Russo²,

Chervo³

et al. 2016

Endocrine-Related Cancer

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“…For instance, 43% of PNETs overexpressed CCND1, which tended to be associated with advanced clinical stage [18] . CCND1 promoter was reported to be stimulated by a large number of transcription factors, mostly c-Fos and c-Jun [16,17] . Activation of CCND1 through progestin has previously been reported in breast cancer [16] , although CCND1 lacks the progesterone response element [19] .…”

mentioning

confidence: 99%

“…Cyclin D1 (CCND1), which regulates the proliferation of cells via the restriction point during the late G1 phase [15] , was reported to be overexpressed in various malignancies [16,17] . For instance, 43% of PNETs overexpressed CCND1, which tended to be associated with advanced clinical stage [18] .…”

mentioning

confidence: 99%

Progesterone Receptor Isoforms A and B in Pancreatic Neuroendocrine Tumor

Yazdani

Kasajima²,

Ogata

et al. 2015

Neuroendocrinology

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Background: Pancreatic neuroendocrine tumors (PNETs) have been reported to express progesterone receptor (PR), and its expression has been demonstrated to be a favorable prognostic factor in these patients. We examined the status of the PR isoforms PRA and PRB in the human PNET cell line and their association with cell proliferation of the tumor cells, which is closely related to the clinical outcome of PNET patients. Methods: Quantitative RT-PCR and cell proliferation assays were performed following treatment with progesterone and RU-486 as a PR antagonist in nontransfected and PRA-transfected cells of the NET cell line QGP-1, which expresses PRB in its native state. PRA, PRB and cyclin D1 (CCND1) were immunolocalized in 87 PNET cases, and the results were compared with clinicopathological parameters. Results: CCND1, c-Fos and c-Jun mRNA levels were all significantly increased by treatment with progesterone in QGP-1 cells with PRB expression compared with PRA-transfected cells (p = 0.02, p = 0.007 and p = 0.001, respectively). The proliferative activity of QGP-1 cells with PRB expression was also significantly stimulated by the administration of progesterone (p = 0.008). PRA immunoreactivity was significantly decreased in higher-grade PNETs (p = 0.04), whereas CCND1 was significantly elevated in higher-grade PNETs (p = 0.035). Conclusion: The results of the present study demonstrate that PRA could play an inhibitory role in the cell proliferation of PNETs, possibly by inhibiting PRB-mediated signals in the presence of progesterone, which could result in decreased CCND1 expression. In addition, the status of PRA in tumor cells could be a prognostic factor in PNETs.

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ERBB2b mRNA isoform encodes a nuclear variant of the ERBB2 oncogene in breast cancer

Hua

Bergon

Cauchy

et al. 2020

J of Cellular Biochemistry

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The presence of nuclear ERBB2 receptor-type tyrosine kinase is one of the causes of the resistance to membrane ERBB2-targeted therapy in breast cancers. It has been previously reported that this nuclear location arises through at least two different mechanisms: proteolytic shedding of the extracellular domain of the full-length receptor and translation of the messenger RNA (mRNA)-encoding ERBB2 from internal initiation codons. Here, we report a new mechanism and function where a significant portion of nuclear ERBB2 results from the translation of the variant ERBB2 mRNA under the transcriptional control of a distal promoter that is actively used in breast cancer cells. We show that both membrane ERBB2a and nuclear ERBB2b isoforms are prevalently expressed in breast cancer cell lines and carcinoma samples. The ERBB2b isoform, which is translated from mRNA variant 2, can directly translocate into the nucleus due to the lack of the signal peptide which is required for an intermediate membrane location. Small interfering RNAmediated gene silencing showed that ERBB2b can repress ERBB2a expression, encoded by variant 1, whereas ERBB2a activates ERBB2b. Nuclear ERBB2 binding to its own promoter was revealed by chromatin immunoprecipitation assay. Altogether, our results provide new insights into the origin and function of nuclear ERBB2 where it can participate at the same time in a positive or a negative feedback autoregulatory loop, dependent on which of its promoters this bona fide transcription factor is acting. They also provide a new understanding for the resistance to therapies targeting the membrane-anchored ERBB2 in breast cancer.

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RETRACTED ARTICLE: Progesterone receptor assembly of a transcriptional complex along with activator protein 1, signal transducer and activator of transcription 3 and ErbB-2 governs breast cancer growth and predicts response to endocrine therapy

Cited by 31 publications

References 76 publications

ErbB-2 nuclear function in breast cancer growth, metastasis and resistance to therapy

ErbB-2 nuclear function in breast cancer growth, metastasis and resistance to therapy

Progesterone Receptor Isoforms A and B in Pancreatic Neuroendocrine Tumor

ERBB2b mRNA isoform encodes a nuclear variant of the ERBB2 oncogene in breast cancer

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