scholarly journals ECT2 associated to PRICKLE1 are poor-prognosis markers in triple-negative breast cancer

2018 ◽  
Author(s):  
Avais M. Daulat ◽  
Pascal Finetti ◽  
Diego Revinski ◽  
Mônica Silveira Wagner ◽  
Luc Camoin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
G Protein ◽  
Poor Prognosis ◽  
Triple Negative ◽  
Molecular Signature ◽  
Breast Cancers ◽  
Nucleotide Exchange ◽  
Small G Protein ◽  
Proteomic Approach

AbstractBackgroundTriple-negative breast cancers are poor-prognosis tumors characterized by absence of molecular signature and are chemotherapy is still the only systemic treatment. Currently, research focus to identify biomarkers that may be usable for prognosis and/or for treatment, notably among the proteins involved in cell migration and metastatic capacity.MethodsWe used proteomic approach to identify protein complexes associated to PRICKLE1 and the mRNA expression level of the corresponding genes in a retrospective series of 8,982 clinically annotated patients with invasive primary breast cancer were assessed. Then, we characterize molecularly the interaction between PRICKLE1 and the guanine nucleotide exchange factor ECT2. Finally, experiments in Xenopus have been carrying out to determine their evolutionary conserved interaction.ResultsWe have identified a network of proteins interacting with the prometastatic scaffold protein PRICKLE1 that includes several small G-protein regulators involved in cell migration and metastasis. Combined analysis expression of PRICKLE1 and small G-protein regulators expression has a strong prognostic value in TNBC. We show that PRICKLE1 controls the activity of ECT2 on RAC1 signaling, a pathway required for cancer cell dissemination.ConclusionsThis work supports the idea that promigratory proteins, which are overexpressed in cancerous epithelium, are suitable pharmaceutical targets.

Claudin 1, 3, 4, and 7 expression in triple-negative breast cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 1070-1070
Author(s):  
Beom Seok Ko ◽  
Hee Jeong Kim ◽  
Jong Han Yu ◽  
jong Won Lee ◽  
Byung Ho Sohn ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Triple Negative Breast Cancer ◽  
Poor Prognosis ◽  
Triple Negative ◽  
Disease Free Survival ◽  
Endocrine Treatment ◽  
Lymph Node Status ◽  
High Recurrence Rate ◽  
Breast Cancers

1070 Background: Triple negative breast cancer (TNBC) often grows rapidly and has poor prognosis, with a high recurrence rate. Because conventional endocrine treatment and HER2 targeted therapy for TNBC is invalid, chemotherapy is the only systemic treatment for TNBC. It is known that several subtypes within the TNBC show different responses to chemotherapy, depending on the subtypes. Recently, a claudin (CLDN) low breast cancer has been identified, exhibiting low expressions of CLDNs 1, 3, 4 and 7. CLDNs are transmembrane proteins that seal tight junctions and are critical for maintaining cell-to-cell adhesion in epithelial cell sheets. However, their role in cancer progression remains largely unexplored. Methods: Surgically removed, formalin-fixed, paraffin-embedded breast cancers from 341 TNBC patients were analyzed to identify CLDN expression.They underwent wide local excision or mastectomy between March, 2004 and December, 2007 at the breast surgery unit of Asan Medical Central Hospital. Results: In our tumor series, we found 45.0% (153/339) of high expressing cases for CLDN1, 57.0% (192/337) for CLDN3, 57.6% (194/337) for CLDN4 and 44.0% (149/339) for CLDN7. Overall, we found 20.5% (70/341) of cases were within the low CLDN expression group and 79.5% (271/341) of tumors were within the high expression group of CLDN1, 3, 4 ,7. Although the high CLDN expression group was significantly associated with positive lymph node status and higher stage, there were no significant differences between CLDN low and high groups in disease free survival (p=0.477) or overall survival (p=0.253). Conclusions: CLDN high tumors are associated with poor prognosis features, but they are not an independent prognostic factor in TNBC patients. However, the mechanisms underlying the different roles of CLDNs in tumorigenesis are largely unclear. Studying the associations of these CLDNs with the TNBC subgroup of breast cancers might provide us with potential diagnostic biomarkers or therapeutic targets for cancer cells.

scholarly journals Role of P-53 Gene in Preventing Breast Cancer

2018 ◽  
Vol 3 (2) ◽  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Inflammatory Breast Cancer ◽  
Poor Prognosis ◽  
Triple Negative ◽  
Type I ◽  
Breast Cancers ◽  
T Helper ◽  
Tp53 Mutations ◽  
Her 2

Breast cancer affects more than one million patients annually in the world and is a leading cause of mortality. Histological type, grade, tumor size, lymph node involvement, and estrogen receptor and HER-2 receptor status, all influence prognosis and the probability of response to systemic therapies. P53 gene is mutated in about 30% of breast cancers/.The possible links between alterations of p53 and clinical or pathological features of breast tumors have been widely investigated. The first study to examine gene-expression patterns of breast cancer suggested that at least four major molecular classes of breast cancer exist: luminal-like, basal-like, normal like, and HER-2 positive. Basal-like breast cancer account for 15% of breast cancers and are often described as triple negative breast cancers (TNBCs). In fact, TNBCs, defined by lack of expression of estrogen receptor, progesterone receptor, and HER2, probably include both basal-like breast cancers and some poorly differentiated luminal breast cancers. They are also associated with a younger age and a poor prognosis. TNBCs also have an increased frequency of TP53 mutations. Recently, it was shown that mutant p53 status was a strongly unfavorable prognostic factor for relapse-free survival and overall survival only in a triple negative group in patients treated with adjuvant anthracycline-containing chemotherapy. Inflammatory breast cancer (IBC) is a clinical diagnosis known as the T4d category in the TNM classification. It is a distinct clinical subtype of locally advanced breast cancer (LABC), with a particularly aggressive behavior and poor prognosis. TP53 mutations are more frequent in inflammatory breast cancer (50%) than in non-inflammatory breast cancer (20–30%). The results from these studies served as the justification for attempts to vaccinate patients using p53-derived peptides, and a number of clinical trials are in progress. The most advanced work used a long synthetic peptide mixture derived from p53 (p53-SLP; Netherlands).The vaccine is delivered in the adjuvant setting and induces T helper type I response in the majority of patients. However, the response may not be potent enough to result in clinical benefit as a mono-therapy because most patients had T-helper cells that failed to produce key cytokines, indicating that this treatment should also be associated with another type of conventional or immunotherapy therapy.

Targeting triple-negative breast cancer by conversion into HER2-positive cancer: A novel therapeutic approach.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e11534-e11534
Author(s):  
Christof Bernemann ◽  
Carolin Huelsewig ◽  
Ludwig Kiesel ◽  
Cornelia Liedtke
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Small Molecule ◽  
Triple Negative Breast Cancer ◽  
Poor Prognosis ◽  
Triple Negative ◽  
Breast Cancer Cell Lines ◽  
Breast Cancers ◽  
Clinical Tool ◽  
Her2 Positive

e11534 Background: Triple negative breast cancer (TNBC) is defined by the lack of estrogen-receptor alpha (ERα) and progesterone receptor (PGR) expression as well as absence of human epidermal growth factor receptor2 (HER2/neu) overexpression. This type of breast cancer is characterized by a poor prognosis and significantly reduced survival rate compared to other BC subtypes. This is mostly due to the lack of targeted agents like endocrine or anti HER2 targets. Breast cancers which overexpress HER2 are usually treated by chemicals targeting HER2; either by blocking the extracellular domain through trastuzumab or the intracellular domain through the small molecule lapatinib. Both therapeutics lead to inhibition of downstream pathways like MAPK and PI3K, resulting in increased apoptosis as well as reduced proliferation. Methods: We hypothesize that downstream effects might be induced in TNBC cells when HER2 is artificially overexpressed and cells get treated as HER2 positive cells. Therefore, triple negative breast cancer cell lines were transfected with HER2. These cells were treated with anti-HER2 agents. Molecular analyses will demonstrate whether transfection with HER2 will yield a HER2 positive breast cancer phenotype in that all downstream signaling mechanisms act similarly to a priori HER2 positive cells. Results: Preliminary experiments suggest that proliferation of TNBC cells transfected with HER2 does not change significantly. Treatment with HER2-blocking antibody trastuzumab leads to significant decrease of proliferation in HER2 transfected, initially triple negative MDA-MB-231 breast cancer cells. Only a moderate decrease in proliferation was observed when lapatinib, a molecule directed against both EGFR and HER2, was used in both MDA-MB-231 wildtype and HER2-transfected cell lines. Conclusions: We surmise that firstly, conversion of cancer might become a clinical tool to treat cancer of poor prognosis and secondly that our results might shed light on future therapeutic approaches e.g. small molecule compound screening for endogenous HER2 reactivation / overexpression and subsequent targeted treatment of triple negative breast cancers.

scholarly journals NOTCH and EZH2 collaborate to repress PTEN expression in breast cancer

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Kyrie Pappas ◽  
Tiphaine C. Martin ◽  
Andrew L. Wolfe ◽  
Christie B. Nguyen ◽  
Tao Su ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Transcriptional Repression ◽  
Poor Prognosis ◽  
Triple Negative ◽  
Fusion Gene ◽  
Pten Expression ◽  
Breast Cancers ◽  
Secretase Inhibitor ◽  
Combined Action ◽  
Almost All

AbstractDownregulation of the PTEN tumor suppressor transcript is frequent in breast cancer and associates with poor prognosis and triple-negative breast cancer (TNBC) when comparing breast cancers to one another. Here we show that in almost all cases, when comparing breast tumors to adjacent normal ducts, PTEN expression is decreased and the PRC2-associated methyltransferase EZH2 is increased. We further find that when comparing breast cancer cases in large cohorts, EZH2 inversely correlates with PTEN expression. Within the highest EZH2 expressing group, NOTCH alterations are frequent, and also associate with decreased PTEN expression. We show that repression of PTEN occurs through the combined action of NOTCH (NOTCH1 or NOTCH2) and EZH2 alterations in a subset of breast cancers. In fact, in cases harboring NOTCH1 mutation or a NOTCH2 fusion gene, NOTCH drives EZH2, HES-1, and HEY-1 expression to repress PTEN transcription at the promoter, which may contribute to poor prognosis in this subgroup. Restoration of PTEN expression can be achieved with an EZH2 inhibitor (UNC1999), a γ-secretase inhibitor (Compound E), or knockdown of EZH2 or NOTCH. These findings elucidate a mechanism of transcriptional repression of PTEN induced by NOTCH1 or NOTCH2 alterations, and identifies actionable signaling pathways responsible for driving a large subset of poor-prognosis breast cancers.

scholarly journals Estrogens and Progestogens in Triple Negative Breast Cancer: Do They Harm?

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2506
Author(s):  
Mark van Barele ◽  
Bernadette A. M. Heemskerk-Gerritsen ◽  
Yvonne V. Louwers ◽  
Mijntje B. Vastbinder ◽  
John W. M. Martens ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative ◽  
Hormone Replacement ◽  
Breast Cancers ◽  
Younger Women ◽  
Alternative Pathways ◽  
Increased Risk ◽  
History Of ◽  
Hormone Sensitive

Triple-negative breast cancers (TNBC) occur more frequently in younger women and do not express estrogen receptor (ER) nor progesterone receptor (PR), and are therefore often considered hormone-insensitive. Treatment of premenopausal TNBC patients almost always includes chemotherapy, which may lead to premature ovarian insufficiency (POI) and can severely impact quality of life. Hormone replacement therapy (HRT) is contraindicated for patients with a history of hormone-sensitive breast cancer, but the data on safety for TNBC patients is inconclusive, with a few randomized trials showing increased risk-ratios with wide confidence intervals for recurrence after HRT. Here, we review the literature on alternative pathways from the classical ER/PR. We find that for both estrogens and progestogens, potential alternatives exist for exerting their effects on TNBC, ranging from receptor conversion, to alternative receptors capable of binding estrogens, as well as paracrine pathways, such as RANK/RANKL, which can cause progestogens to indirectly stimulate growth and metastasis of TNBC. Finally, HRT may also influence other hormones, such as androgens, and their effects on TNBCs expressing androgen receptors (AR). Concluding, the assumption that TNBC is completely hormone-insensitive is incorrect. However, the direction of the effects of the alternative pathways is not always clear, and will need to be investigated further.

scholarly journals INPP4B promotes PI3Kα-dependent late endosome formation and Wnt/β-catenin signaling in breast cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Samuel J. Rodgers ◽  
Lisa M. Ooms ◽  
Viola M. J. Oorschot ◽  
Ralf B. Schittenhelm ◽  
Elizabeth V. Nguyen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Akt Signaling ◽  
Late Endosome ◽  
Breast Cancers ◽  
Lysosomal Degradation ◽  
Late Endosomes ◽  
Mrna And Protein Expression

AbstractINPP4B suppresses PI3K/AKT signaling by converting PI(3,4)P2 to PI(3)P and INPP4B inactivation is common in triple-negative breast cancer. Paradoxically, INPP4B is also a reported oncogene in other cancers. How these opposing INPP4B roles relate to PI3K regulation is unclear. We report PIK3CA-mutant ER+ breast cancers exhibit increased INPP4B mRNA and protein expression and INPP4B increased the proliferation and tumor growth of PIK3CA-mutant ER+ breast cancer cells, despite suppression of AKT signaling. We used integrated proteomics, transcriptomics and imaging to demonstrate INPP4B localized to late endosomes via interaction with Rab7, which increased endosomal PI3Kα-dependent PI(3,4)P2 to PI(3)P conversion, late endosome/lysosome number and cargo trafficking, resulting in enhanced GSK3β lysosomal degradation and activation of Wnt/β-catenin signaling. Mechanistically, Wnt inhibition or depletion of the PI(3)P-effector, Hrs, reduced INPP4B-mediated cell proliferation and tumor growth. Therefore, INPP4B facilitates PI3Kα crosstalk with Wnt signaling in ER+ breast cancer via PI(3,4)P2 to PI(3)P conversion on late endosomes, suggesting these tumors may be targeted with combined PI3K and Wnt/β-catenin therapies.

scholarly journals The mitotic checkpoint is a targetable vulnerability of carboplatin-resistant triple negative breast cancers

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Stijn Moens ◽  
Peihua Zhao ◽  
Maria Francesca Baietti ◽  
Oliviero Marinelli ◽  
Delphi Van Haver ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative ◽  
Breast Cancer Subtype ◽  
Mitotic Checkpoint ◽  
Breast Cancers ◽  
Checkpoint Kinases ◽  
Xenograft Models ◽  
Potential Strategy ◽  
Shrna Screen ◽  
Resistant Cells

AbstractTriple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, lacking effective therapy. Many TNBCs show remarkable response to carboplatin-based chemotherapy, but often develop resistance over time. With increasing use of carboplatin in the clinic, there is a pressing need to identify vulnerabilities of carboplatin-resistant tumors. In this study, we generated carboplatin-resistant TNBC MDA-MB-468 cell line and patient derived TNBC xenograft models. Mass spectrometry-based proteome profiling demonstrated that carboplatin resistance in TNBC is linked to drastic metabolism rewiring and upregulation of anti-oxidative response that supports cell replication by maintaining low levels of DNA damage in the presence of carboplatin. Carboplatin-resistant cells also exhibited dysregulation of the mitotic checkpoint. A kinome shRNA screen revealed that carboplatin-resistant cells are vulnerable to the depletion of the mitotic checkpoint regulators, whereas the checkpoint kinases CHEK1 and WEE1 are indispensable for the survival of carboplatin-resistant cells in the presence of carboplatin. We confirmed that pharmacological inhibition of CHEK1 by prexasertib in the presence of carboplatin is well tolerated by mice and suppresses the growth of carboplatin-resistant TNBC xenografts. Thus, abrogation of the mitotic checkpoint by CHEK1 inhibition re-sensitizes carboplatin-resistant TNBCs to carboplatin and represents a potential strategy for the treatment of carboplatin-resistant TNBCs.

scholarly journals Triple negative aggressive phenotype controlled by miR-135b and miR-365: new theranostics candidates

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Gloria Bertoli ◽  
Claudia Cava ◽  
Fabio Corsi ◽  
Francesca Piccotti ◽  
Cristina Martelli ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Triple Negative ◽  
Differentially Expressed ◽  
Tumor Control ◽  
Breast Cancers ◽  
Basal Breast Cancer ◽  
Therapeutic Molecules ◽  
Invasive Capacity ◽  
Tnbc Subtype

AbstractTriple negative breast cancer (TNBC) accounts for about a fifth of all breast cancers and includes a diverse group of cancers. The heterogeneity of TNBC and the lack of target receptors on the cell surface make it difficult to develop specific therapeutic treatments. These aspects cause the high negative prognosis of patients with this type of tumor. The analysis of the molecular profiles of TNBC samples has allowed a better characterization of this tumor, supporting the search for new reliable diagnostic markers. To this end, we have developed a bioinformatic approach to integrate networks of genes differentially expressed in basal breast cancer compared to healthy tissues, with miRNAs able to regulate their expression. We studied the role of these miRNAs in TNBC subtype cell lines. We therefore identified two miRNAs, namely miR-135b and miR-365, with a central role in regulating the altered functional pathways in basal breast cancer. These two miRNAs are differentially expressed in human TNBC immunohistochemistry-selected tissues, and their modulation has been shown to play a role in the proliferation of tumor control and its migratory and invasive capacity in TNBC subtype cell lines. From the perspective of personalized medicine, we managed to modulate the expression of the two miRNAs in organotypic cultures, suggesting their possible use as diagnostic and therapeutic molecules. miR-135b and miR-365 have a key role in TNBC, controlling proliferation and invasion. Their detection could be helpful in TNBC diagnosis, while their modulation could become a new therapeutic tool for TNBC.

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