scholarly journals MYC pathway activation in triple-negative breast cancer is synthetic lethal with CDK inhibition

2012 ◽  
Vol 209 (4) ◽  
pp. 679-696 ◽  
Author(s):  
Dai Horiuchi ◽  
Leonard Kusdra ◽  
Noelle E. Huskey ◽  
Sanjay Chandriani ◽  
Marc E. Lenburg ◽  
...  
Keyword(s):  
Triple Negative ◽  
Tumor Regression ◽  
Breast Tumors ◽  
Breast Cancers ◽  
Her2 Receptor ◽  
Altered Expression ◽  
Synthetic Lethal ◽  
Pathway Activation ◽  
Triple Negative Tumor ◽  
Negative Tumor

Estrogen, progesterone, and HER2 receptor-negative triple-negative breast cancers encompass the most clinically challenging subtype for which targeted therapeutics are lacking. We find that triple-negative tumors exhibit elevated MYC expression, as well as altered expression of MYC regulatory genes, resulting in increased activity of the MYC pathway. In primary breast tumors, MYC signaling did not predict response to neoadjuvant chemotherapy but was associated with poor prognosis. We exploit the increased MYC expression found in triple-negative breast cancers by using a synthetic-lethal approach dependent on cyclin-dependent kinase (CDK) inhibition. CDK inhibition effectively induced tumor regression in triple-negative tumor xenografts. The proapoptotic BCL-2 family member BIM is up-regulated after CDK inhibition and contributes to this synthetic-lethal mechanism. These results indicate that aggressive breast tumors with elevated MYC are uniquely sensitive to CDK inhibitors.

Molecular profiling of triple-negative endometrial cancers (TNEC) and triple-negative breast cancers (TNBC) to reveal unique expression profiles.

2015 ◽  
Vol 33 (28_suppl) ◽  
pp. 159-159
Author(s):  
Nathaniel L. Jones ◽  
Joanne Xiu ◽  
Sandeep K. Reddy ◽  
Jason Dennis Wright ◽  
William M. Burke ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endometrial Cancer ◽  
Protein Expression ◽  
Triple Negative ◽  
Expression Profiles ◽  
Receptor Expression ◽  
Mutation Rates ◽  
Breast Cancers ◽  
Her2 Receptor ◽  
Molecular Features

159 Background: “Triple negative” has been used to characterize a subtype of breast cancer that lacks estrogen, progesterone, and HER2 receptor expression. They are aggressive cancers with limited treatment options. It’s unknown if similar phenotype found in other cancer types, like endometrial cancer, harbor similar molecular alterations and prognosis. We aim to compare molecular features between TNEC and TNBC. Methods: A total of 3133 endometrial cancer samples were evaluated by Caris Life Sciences (Phoenix, AZ) from Mar, 2011 to Jul, 2014 by multiplatform profiling, which included a combination of sequencing (Sanger or NGS), protein expression (IHC), and/or gene amplification (CISH or FISH). 545 TNEC and 2049 TNBC were identified based on reported pathology and compared using Fisher exact tests. Results: Compared to an incidence of 15-20% TNBC in breast cancer, 17% (545/3133) TNEC was seen in our cohort, of which 13% were endometrioid, 22% serous, 26% carcinosarcoma, 7% clear cell, and 22% other. Compared with TNBC, TNEC showed 1.9 exonic mutations per case while TNBC showed 1.2 mutations per case. As shown in the table, AR expression is lower in TNEC than TNBC. TP53 mutation was common in both but more frequent in TNBC. While BRCA1/2 mutation rates were similar, low MGMT and ERCC1 were more common in TNEC, suggesting increased aberrant DNA repair. DNA synthesis protein expression was higher in TNEC including TS, RRM1, and TOPO2A, although TNBC had higher TOPO1. PD-1 expression was more common in TNEC suggesting immune pathway involvement. PI3K/AKT/mTor, MAPK and Wnt pathways were more involved in TNEC with greater PTEN, PIK3CA, FBXW7, KRAS and CTNNB1 mutations. Conclusions: Our study reveals significantly higher overall mutation rates in TNEC than TNBC, and specifically higher activations of multiple molecular pathways including PI3K/Akt/mTor, MAPK and Wnt. Further studies are warranted to validate these findings in clinical trials.

Association of hypoxia-induced centrosome amplification with clinical outcomes in triple-negative breast cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e23170-e23170
Author(s):  
Karuna Mittal ◽  
Da Hoon Choi ◽  
Angela Ogden ◽  
Brian D Melton ◽  
Meenakshi Vij Gupta ◽  
...  
Keyword(s):  
Gene Expression ◽  
Triple Negative ◽  
Gene Expression Signature ◽  
Breast Tumors ◽  
Centrosome Amplification ◽  
Strong Positive Correlation ◽  
Breast Cancers ◽  
Tissue Samples ◽  
Hypoxic Conditions ◽  
Cells Cultured

e23170 Background: Centrosome amplification (CA) which refers to presence of supernumerary or abnormally large centrosomes is believed to drive tumor progression by promoting chromosomal instability and the generation of aggressive tumor clones that are more capable of rapid metastasis. Not much is known about factors that drive CA within solid tumors. We have previously shown the existence of rampant CA in triple-negative breast cancers (TNBCs).We report here thatintratumoral hypoxia, which is one of the major contributors to tumor heterogeneity, induces CA in TNBCs via HIF-1α. Methods: We immunohistochemically labeled 24 TNBC and adjacent normal tissue samples for HIF-1α and derived weighted indices (WIs) for nuclear HIF-1α. Adjacent serial sections from the same tumors were immunofluorescently labeled for the centrosomal marker γ-tubulin and CA was determined. Using public microarray datasets (Kao dataset, n = 327), we investigated whether centrosomal gene expression is enriched in breast tumors characterized by a hypoxia gene expression signature. Finally, to test the role of hypoxia in CA induction we exposed cultured TNBC cells (MDA-MB-231 and MDA-MB-468) to hypoxia and overexpressed (OE) or knocked out (KO) HIF-1α and quantitated CA. Results: A strong positive correlation was found between nuclear HIF-1α WI and CA in TNBC samples (Spearman’s rho p = 0.722, p < 0.001), and higher nuclear HIF-1α was associated with worse overall survival (p = 0.041; HR = 1.03). Furthermore, breast tumors with high expression of hypoxia-associated genes exhibited higher expression of centrosomal genes than breast tumors with low expression of hypoxia-associated genes. TNBC cells cultured in hypoxic conditions exhibited ~1.5 fold higher (p < 0.05) CA compared to cells cultured in normoxic conditions. Interestingly, level of CA decreased when HIF-1α KO TNBC cells were exposed to hypoxia; conversely, CA increased when HIF-1α OE TNBC cells were cultured in normoxic conditions. Conclusions: Thus,intratumoral hypoxia drives CA in TNBC via HIF-1α and contributes to poor outcomes. Determination of CA may help identify TNBC patients who could benefit from centrosome declustering drugs and HIF-1α inhibitors.

Parthenolide and its Analogues: A New Potential Strategy for the Treatment of Triple-Negative Breast Tumors

2020 ◽  
Vol 27 (39) ◽  
pp. 6628-6642
Author(s):  
Thaise Gonçalves Araújo ◽  
Lara Vecchi ◽  
Paula Marynella Alves Pereira Lima ◽  
Everton Allan Ferreira ◽  
Igor Moreira Campos ◽  
...  
Keyword(s):  
Clinical Characteristics ◽  
Triple Negative ◽  
Breast Tumors ◽  
Systemic Effects ◽  
Breast Cancers ◽  
Antitumor Effects ◽  
Tnbc Cell ◽  
Transcriptional Changes ◽  
Potential Strategy ◽  
Molecular Patterns

Triple Negative Breast Cancers (TNBC) are heterogeneous and aggressive pathologies, with distinct morphological and clinical characteristics associated with their genetic diversity, epigenetics, transcriptional changes and aberrant molecular patterns. Treatment with anti-neoplastic drugs exerts systemic effects with low specificity, and incipient improvement in overall survival due to chemoresistance and recurrence. New alternatives for TNBC treatment are urgent and parthenolide or its analogues have been explored. Parthenolide is a sesquiterpene lactone with promising antitumor effects against TNBC cell lines. This review highlights the importance of parthenolide and its analogue drugs in TNBC treatment.

scholarly journals P-Rex1 Expression in Invasive Breast Cancer in relation to Receptor Status and Distant Metastatic Site

2017 ◽  
Vol 2017 ◽  
pp. 1-6 ◽  
Author(s):  
Jonathan D. Marotti ◽  
Kristen E. Muller ◽  
Laura J. Tafe ◽  
Eugene Demidenko ◽  
Todd W. Miller
Keyword(s):  
Breast Cancer ◽  
Triple Negative ◽  
Breast Tumors ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Solid Organ ◽  
Breast Cancers ◽  
Primary Tumors ◽  
Receptor Status ◽  
Cancer Subtypes

Background. Phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 1 (P-Rex1) has been implicated in cancer growth, metastasis, and response to phosphatidylinositol 3-kinase (PI3K) inhibitor therapy. The aim of this study was to determine whether P-Rex1 expression differs between primary and metastatic human breast tumors and between breast cancer subtypes. Design. P-Rex1 expression was measured in 133 specimens by immunohistochemistry: 40 and 42 primary breast tumors from patients who did versus did not develop metastasis, respectively, and 51 breast-derived tumors from metastatic sites (36 of which had matching primary tumors available for analysis). Results. Primary breast tumors showed significant differences in P-Rex1 expression based on receptor subtype. ER+ and HER2+ primary tumors showed higher P-Rex1 expression than primary triple-negative tumors. HER2+ metastases from all sites showed significantly higher P-Rex1 expression compared to other metastatic receptor subtypes. Solid organ (i.e., brain, lung, and liver) metastases showed higher P-Rex1 expression compared to bone metastases. Conclusions. P-Rex1 expression is increased in ER+ and HER2+ breast cancers compared to triple-negative tumors. P-Rex1 may be differentially expressed in metastatic tumors based on site and receptor status. The role of P-Rex1 in the development of breast cancer metastases and as a predictive biomarker of therapeutic response warrants further investigation.

scholarly journals A Review of the Potential Role of Human Cytomegalovirus (HCMV) Infections in Breast Cancer Carcinogenesis and Abnormal Immunity

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1842 ◽  
Author(s):  
Jürgen Geisler ◽  
Joel Touma ◽  
Afsar Rahbar ◽  
Cecilia Söderberg-Nauclér ◽  
Katja Vetvik
Keyword(s):  
Breast Cancer ◽  
Human Cytomegalovirus ◽  
Triple Negative ◽  
Breast Tumors ◽  
Active Role ◽  
Gene Products ◽  
Breast Cancers ◽  
Wide Range

Previously recognized classical human onco-viruses can regulate complex neoplastic events, and are estimated to play a role during carcinogenesis in 15–20% of cancer cases. Although the DNA and gene products of several viruses have been found in breast tumors, none of the classical onco-viruses have definitely been linked to the initiation of breast cancer. However, recent evidence shows that human cytomegalovirus (HCMV) gene products are found in >90% of tumors and metastases of breast cancers, and their increased expression can be correlated to a more aggressive breast cancer phenotype. Supporting the active role of HCMV in breast cancer, a specific HCMV strain, HCMV-DB, was recently shown to exert oncogenic transformational activity in breast epithelial cells in vitro, and to give rise to fast-growing, triple-negative breast tumors when injected into immune deficient mice. The same observation holds true for clinical studies implying increased HCMV protein expression in triple negative breast cancer biopsies. In addition to functionally being able to hijack tumor-promoting cellular events, HCMV is known to exhibit a wide range of immunosuppressive effects, which can have radical impact on the tumor microenvironment. HCMV infected cells can avoid recognition and elimination by the immune system by orchestrating polarization of immunosuppressive type II macrophages, preventing antigen presentation, by expressing T cell inhibitory molecules, and possibly, by the induction of regulatory T (Treg) cell responses. These actions would be especially deleterious for the antigenic activation and proliferation of tumor specific CD8+ cytotoxic T lymphocytes (CTLs), whose effector functions have recently been targeted by successful, experimental immunotherapy protocols. The recognition of alternative causes and drivers of breast cancer is a pivotal research topic for the development of diagnostics and novel, effective preventive and therapeutic strategies targeting both tumor cells and their microenvironments.

scholarly journals REVIEW ON POTENTIAL TARGETED THERAPY FOR TRIPLE NEGATIVE BREAST CANCER

2020 ◽  
Vol 5 (2) ◽  
pp. 55-60
Author(s):  
Nurul Issttifa Aminuddin ◽  
Raihana Edros ◽  
Rajaletchumy Veloo Kutty
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Targeted Therapies ◽  
Triple Negative ◽  
Treatment Options ◽  
Molecular Targets ◽  
Single Type ◽  
Triple Negative Tumor ◽  
Negative Tumor ◽  
Potential Opportunity

Triple negative breast cancer (TNBC) is a very aggressive type of cancer.  TNBC is not just a single type of disease to be cured, but it consists of 6 subtypes which are basal-like 1 and 2, immunomodulatory, mesenchymal, mesenchymal stem- like and luminar androgen receptor. These subtypes has diverse characteristics, which hold potential opportunity for targeted treatment. Lack of molecular targets for triple negative tumor lead to limited targeted therapies for TNBC.  Therefore, effective targeted therapies are urgently needed for TNBC. This paper will highlight on the potential targets in TNBC and treatment options that are currently under clinical application.  

Retrospective comparisons of nanoparticle albumin-bound paclitaxel and docetaxel neoadjuvant regimens for breast cancer

Nanomedicine ◽  
2021 ◽  
Vol 16 (5) ◽  
pp. 391-400
Author(s):  
Yan Li ◽  
Xiang Chen ◽  
Qiannan Zhu ◽  
Rui Chen ◽  
Lu Xu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative ◽  
Pathological Complete Response ◽  
Response Rates ◽  
Complete Response ◽  
Neoadjuvant Systemic Therapy ◽  
Triple Negative Tumor ◽  
Negative Tumor ◽  
Dose Dense ◽  
Peripheral Sensory

Aim: To compare the efficacy and safety of 2-weekly nanoparticle albumin-bound paclitaxel (nP) and 3-weekly docetaxel regimens as neoadjuvant systemic therapy (NST) for breast cancer. Materials & methods: Patients (n = 201) received NST comprising either dose-dense epirubicin and cyclophosphamide followed by 2-weekly nP (n = 104) or 3-weekly courses of epirubicin and cyclophosphamide followed by docetaxel (n = 97). Results: Higher pathological complete response rates were achieved by the nP group. Subgroup analysis showed that the nP-based regimen achieved higher pathological complete response rates in patients with triple-negative tumor cells and high Ki67 levels. However, grades 3–4 peripheral sensory neuropathies were more frequent in the nP group. Conclusion: The 2-weekly nP-based regimen might be a better choice of NST for patients with breast cancer.

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