scholarly journals Type 1 Nuclear Receptor Activity in Breast Cancer: Translating Preclinical Insights to the Clinic

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4972
Author(s):  
Sanjeev Kumar ◽  
Allegra Freelander ◽  
Elgene Lim
Keyword(s):  
Breast Cancer ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Patient Outcomes ◽  
Estrogen Receptor Α ◽  
Receptor Activity ◽  
Breast Cancers ◽  
Cancer Subtypes ◽  
Major Breast

The nuclear receptor (NR) family of transcription factors is intimately associated with the development, progression and treatment of breast cancer. They are used diagnostically and prognostically, and crosstalk between nuclear receptor pathways and growth factor signalling has been demonstrated in all major subtypes of breast cancer. The majority of breast cancers are driven by estrogen receptor α (ER), and anti-estrogenic therapies remain the backbone of treatment, leading to clinically impactful improvements in patient outcomes. This serves as a blueprint for the development of therapies targeting other nuclear receptors. More recently, pivotal findings into modulating the progesterone (PR) and androgen receptors (AR), with accompanying mechanistic insights into NR crosstalk and interactions with other proliferative pathways, have led to clinical trials in all of the major breast cancer subtypes. A growing body of evidence now supports targeting other Type 1 nuclear receptors such as the glucocorticoid receptor (GR), as well as Type 2 NRs such as the vitamin D receptor (VDR). Here, we reviewed the existing preclinical insights into nuclear receptor activity in breast cancer, with a focus on Type 1 NRs. We also discussed the potential to translate these findings into improving patient outcomes.

Recent progress in immunotherapy of breast cancer targeting the human epidermal growth factor receptor 2 (HER2)

2021 ◽  
pp. 107815522199163
Author(s):  
Homa Seyedmirzaei ◽  
Mahsa Keshavarz-Fathi ◽  
Sepideh Razi ◽  
Masoumeh Gity ◽  
Nima Rezaei
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
New Drugs ◽  
Breast Cancers ◽  
Cancer Subtypes ◽  
Drug Conjugates ◽  
Heavy Burden ◽  
Epidermal Growth

Objective Breast cancer is responsible for most of the cancer-induced deaths in women around the world. The current review will discuss different approaches of targeting HER2, an epidermal growth factor overexpressed in 30% of breast cancer cases. Data sources We conducted a search on Pubmed and Scopus databases to find studies relevant to HER2+ breast cancers and targeting HER2 as means of immunotherapy. Out of 1043 articles, 105 studies were included in this review. Data summary As well as the introduction of HER2 and breast cancer subtypes, we discussed various aspects of HER2-targeting immunotherapy including monoclonal antibodies, Antibody-drug conjugates (ADCs), Chimeric Antigen Receptor (CAR) T-cells and vaccines. Conclusions Despite several ways of controlling breast cancer, the need to investigate new drugs and approaches seems to be much significant as this cancer still has a heavy burden on people’s health and survival.

scholarly journals Crosstalk between HER2 and PD-1/PD-L1 in Breast Cancer: From Clinical Applications to Mathematical Models

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 636 ◽  
Author(s):  
Regina Padmanabhan ◽  
Hadeel Shafeeq Kheraldine ◽  
Nader Meskin ◽  
Semir Vranic ◽  
Ala-Eddin Al Moustafa
Keyword(s):  
Breast Cancer ◽  
Mathematical Models ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Breast Cancers ◽  
Treatment Protocols ◽  
Cancer Subtypes ◽  
Cancer Management ◽  
Her2 Breast Cancer ◽  
Programmed Death

Breast cancer is one of the major causes of mortality in women worldwide. The most aggressive breast cancer subtypes are human epidermal growth factor receptor-positive (HER2+) and triple-negative breast cancers. Therapies targeting HER2 receptors have significantly improved HER2+ breast cancer patient outcomes. However, several recent studies have pointed out the deficiency of existing treatment protocols in combatting disease relapse and improving response rates to treatment. Overriding the inherent actions of the immune system to detect and annihilate cancer via the immune checkpoint pathways is one of the important hallmarks of cancer. Thus, restoration of these pathways by various means of immunomodulation has shown beneficial effects in the management of various types of cancers, including breast. We herein review the recent progress in the management of HER2+ breast cancer via HER2-targeted therapies, and its association with the programmed death receptor-1 (PD-1)/programmed death ligand-1 (PD-L1) axis. In order to link research in the areas of medicine and mathematics and point out specific opportunities for providing efficient theoretical analysis related to HER2+ breast cancer management, we also review mathematical models pertaining to the dynamics of HER2+ breast cancer and immune checkpoint inhibitors.

scholarly journals Epigenetic Regulation of Immunotherapy Response in Triple-Negative Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4139
Author(s):  
Pere Llinàs-Arias ◽  
Sandra Íñiguez-Muñoz ◽  
Kelly McCann ◽  
Leonie Voorwerk ◽  
Javier I. J. Orozco ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Immune Escape ◽  
Checkpoint Inhibitors ◽  
Early Stage ◽  
Regulatory Elements ◽  
Her2 Overexpression ◽  
Breast Cancers ◽  
Cancer Subtypes

Triple-negative breast cancer (TNBC) is defined by the absence of estrogen receptor and progesterone receptor and human epidermal growth factor receptor 2 (HER2) overexpression. This malignancy, representing 15–20% of breast cancers, is a clinical challenge due to the lack of targeted treatments, higher intrinsic aggressiveness, and worse outcomes than other breast cancer subtypes. Immune checkpoint inhibitors have shown promising efficacy for early-stage and advanced TNBC, but this seems limited to a subgroup of patients. Understanding the underlying mechanisms that determine immunotherapy efficiency is essential to identifying which TNBC patients will respond to immunotherapy-based treatments and help to develop new therapeutic strategies. Emerging evidence supports that epigenetic alterations, including aberrant chromatin architecture conformation and the modulation of gene regulatory elements, are critical mechanisms for immune escape. These alterations are particularly interesting since they can be reverted through the inhibition of epigenetic regulators. For that reason, several recent studies suggest that the combination of epigenetic drugs and immunotherapeutic agents can boost anticancer immune responses. In this review, we focused on the contribution of epigenetics to the crosstalk between immune and cancer cells, its relevance on immunotherapy response in TNBC, and the potential benefits of combined treatments.

scholarly journals Review of: Tamoxifen and TRAIL synergistically induce apoptosis in breast cancer cells

2008 ◽  
Vol 11 (2) ◽  
Author(s):  
Alison J. Butt
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Single Agent ◽  
Xenograft Model ◽  
Estrogen Receptor Α ◽  
Tumor Xenograft ◽  
Breast Cancers ◽  
Induced Apoptosis

Citation of original article:C. Lagadec, E. Adriaenssens, R. A. Toillon, V. Chopin, R. Romon, F. Van Coppenolle, H. Hondermarck, X. Le Bourhis. Oncogene advance online publication, 3 September 2007; doi:10.1038/sj.onc.1210749.Abstract of the original article:Tamoxifen (TAM), is widely used as a single agent in adjuvant treatment of breast cancer. Here, we investigated the effects of TAM in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in estrogen receptor-α (ER-α)-positive and -negative breast cancer cells. We showed that cotreatment with TAM and TRAIL synergistically induced apoptosis regardless of ER-α status. By contrast, cotreatment did not affect the viability of normal breast epithelial cells. Cotreatment with TAM and TRAIL in breast cancer cells decreased the levels of antiapoptotic proteins including FLIPs and Bcl-2, and enhanced the levels of proapoptotic proteins such as FADD, caspase 8, tBid, Bax and caspase 9. Furthermore, cotreatment-induced apoptosis was efficiently reduced by FADD- or Bid-siRNA, indicating the implication of both extrinsic and intrinsic pathways in synergistic apoptosis induction. Importantly, cotreatment totally arrested tumor growth in an ER-α-negative MDA-MB-231 tumor xenograft model. The abrogation of tumor growth correlated with enhanced apoptosis in tumor tissues. Our findings raise the possibility to use TAM in combination with TRAIL for breast cancers, regardless of ER-α status.

scholarly journals Ki67 index in intrinsic breast cancer subtypes and its association with prognostic parameters

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Atif Ali Hashmi ◽  
Kashif Ali Hashmi ◽  
Muhammad Irfan ◽  
Saadia Mehmood Khan ◽  
Muhammad Muzzammil Edhi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ductal Carcinoma ◽  
Prognostic Significance ◽  
Breast Cancer Subtypes ◽  
Prognostic Parameters ◽  
Ki67 Index ◽  
Breast Cancers ◽  
Cancer Subtypes ◽  
Luminal B ◽  
Cancer Management

Abstract Objectives Ki67 is the most commonly used marker to evaluate proliferative index in breast cancer, however no cutoff values have been clearly defined for high ki67 index. Cancer management should be according to loco-regional profile; therefore, we aimed to determine ki67 index in 1951 cases of intrinsic breast cancer subtypes and its association with other prognostic parameters in our set up. Results Triple negative breast cancers showed highest ki67 index (mean 50.9 ± 23.7%) followed by Her2neu (mean 42.6 ± 21.6%) and luminal B cancers (mean 34.9 ± 20.05%). Metaplastic and medullary breast cancers significantly showed higher ki67 index as compared to ductal carcinoma, NOS. No significant association of ki67 index was noted with any of the histologic parameters in different subtypes of breast cancer expect for tumor grade. Although, ki67 index is a valuable biomarker in breast cancer, however no independent prognostic significance of ki67 could be established in our study.

scholarly journals Genomic Signatures in Luminal Breast Cancer

Breast Care ◽  
2020 ◽  
Vol 15 (4) ◽  
pp. 355-365
Author(s):  
Julian Puppe ◽  
Tabea Seifert ◽  
Christian Eichler ◽  
Henryk Pilch ◽  
Peter Mallmann ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Throughput Sequencing ◽  
Early Stage ◽  
Intrinsic Subtype ◽  
Luminal Breast Cancer ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Cancer Subtypes ◽  
Molecular Tests ◽  
Immunohistochemical Markers

Background: Breast cancer is a very heterogeneous disease and luminal breast carcinomas represent the hormone receptor-positive tumors among all breast cancer subtypes. In this context, multigene signatures were developed to gain further prognostic and predictive information beyond clinical parameters and traditional immunohistochemical markers. Summary: For early breast cancer patients these molecular tools can guide clinicians to decide on the extension of endocrine therapy to avoid over- and undertreatment by adjuvant chemotherapy. Beside the predictive and prognostic value, a few genomic tests are also able to provide intrinsic subtype classification. In this review, we compare the most frequently used and commercially available molecular tests (OncotypeDX®, MammaPrint®, Prosigna®, EndoPredict®, and Breast Cancer IndexSM). Moreover, we discuss the clinical utility of molecular profiling for advanced breast cancer of the luminal subtype. Key Messages: Multigene assays can help to de-escalate systemic therapy in early-stage breast cancer. Only the Oncotype DX® and MammaPrint®test are validated by entirely prospective and randomized phase 3 trials. More clinical evidence is needed to support the use of genomic tests in node-positive disease. Recent developments in high-throughput sequencing technology will provide further insights to understand the heterogeneity of luminal breast cancers in early-stage and metastatic disease.

scholarly journals ER-Negative Breast Cancer Is Highly Responsive to Cholesterol Metabolite Signalling

Nutrients ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 2618 ◽  
Author(s):  
Samantha A Hutchinson ◽  
Priscilia Lianto ◽  
Hanne Roberg-Larsen ◽  
Sebastiano Battaglia ◽  
Thomas A Hughes ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Target Genes ◽  
Cholesterol Metabolism ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Cancer Subtypes ◽  
Hormone Receptor Positive ◽  
Er Positive ◽  
Positive Breast Cancer

Interventions that alter cholesterol have differential impacts on hormone receptor positive- and negative-breast cancer risk and prognosis. This implies differential regulation or response to cholesterol within different breast cancer subtypes. We evaluated differences in side-chain hydroxycholesterol and liver X nuclear receptor signalling between Oestrogen Receptor (ER)-positive and ER-negative breast cancers and cell lines. Cell line models of ER-positive and ER-negative disease were treated with Liver X Receptor (LXR) ligands and transcriptional activity assessed using luciferase reporters, qPCR and MTT. Publicly available datasets were mined to identify differences between ER-negative and ER-positive tumours and siRNA was used to suppress candidate regulators. Compared to ER-positive breast cancer, ER-negative breast cancer cells were highly responsive to LXR agonists. In primary disease and cell lines LXRA expression was strongly correlated with its target genes in ER-negative but not ER-positive disease. Expression of LXR’s corepressors (NCOR1, NCOR2 and LCOR) was significantly higher in ER-positive disease relative to ER-negative, and their knock-down equalized sensitivity to ligand between subtypes in reporter, gene expression and viability assays. Our data support further evaluation of dietary and pharmacological targeting of cholesterol metabolism as an adjunct to existing therapies for ER-negative and ER-positive breast cancer patients.

scholarly journals Identification of Long Noncoding RNAs as Predictors of Survival in Triple-Negative Breast Cancer Based on Network Analysis

2020 ◽  
Vol 2020 ◽  
pp. 1-15 ◽  
Author(s):  
Xiao-Xiao Li ◽  
Li-Juan Wang ◽  
Jie Hou ◽  
Hong-Yang Liu ◽  
Rui Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Network Analysis ◽  
Molecular Mechanisms ◽  
Triple Negative ◽  
Noncoding Rnas ◽  
Long Noncoding Rnas ◽  
Breast Cancers ◽  
Luminal A ◽  
Her2 Positive ◽  
Cancer Subtypes

Breast cancer is the most common cancer observed in adult females, worldwide. Due to the heterogeneity and varied molecular subtypes of breast cancer, the molecular mechanisms underlying carcinogenesis in different subtypes of breast cancer are distinct. Recently, long noncoding RNAs (lncRNAs) have been shown to be oncogenic or play important roles in cancer suppression and are used as biomarkers for diagnosis and therapy. In this study, we identified 134 lncRNAs and 6,414 coding genes were differentially expressed in triple-negative (TN), human epidermal growth factor receptor 2- (HER2-) positive, luminal A-positive, and luminal B-positive breast cancer. Of these, 37 lncRNAs were found to be dysregulated in all four subtypes of breast cancers. Subtypes of breast cancer special modules and lncRNA-mRNA interaction networks were constructed through weighted gene coexpression network analysis (WGCNA). Survival analysis of another public datasets was used to verify the identified lncRNAs exhibiting potential indicative roles in TN prognosis. Results from heat map analysis of the identified lncRNAs revealed that five blocks were significantly displayed. High expressions of lncRNAs, including LINC00911, CSMD2-AS1, LINC01192, SNHG19, DSCAM-AS1, PCAT4, ACVR28-AS1, and CNTFR-AS1, and low expressions of THAP9-AS1, MALAT1, TUG1, CAHM, FAM2011, NNT-AS1, COX10-AS1, and RPARP-AS1 were associated with low survival possibility in TN breast cancers. This study provides novel lncRNAs as potential biomarkers for the therapeutic and prognostic classification of different breast cancer subtypes.

Breast cancer subtypes in Chinese Americans: A study from the Mount Sinai Health System.

2014 ◽  
Vol 32 (26_suppl) ◽  
pp. 39-39
Author(s):  
Camila Masias ◽  
Theresa H. Shao
Keyword(s):  
Breast Cancer ◽  
Lymph Node ◽  
Chinese Americans ◽  
Breast Cancer Subtypes ◽  
Age At Diagnosis ◽  
Chinese Patients ◽  
Breast Cancers ◽  
Cancer Subtypes ◽  
Her2 Breast Cancer ◽  
Mount Sinai

39 Background: Breast cancer has been increasing in many Asian countries, as well as among Asian Americans. While many studies have examined breast cancer subtypes in African American and Caucasian populations, few have looked at tumor subtypes in the Asian population. We aimed to examine breast cancer subtypes in Chinese Americans. Methods: We identified all Chinese patients diagnosed with invasive breast cancers between 2005 and 2012 from the Cancer Registry of Mount Sinai Beth Israel, Mount Sinai St. Luke’s, and Roosevelt Hospitals. The following clinical data were collected for each patient: age at diagnosis, year of diagnosis, largest tumor size (cm), lymph node status, estrogen receptor (ER), progesterone receptor (PR) and HER2 status. Based on ER, PR, and HER2, patients were categorized into three molecular subtypes: 1) Hormone receptor (HR)+ (ER and/or PR positive, HER2 negative), HER2+ and triple negative (TN) (ER, PR, and HER2 negative). Descriptive variables were analyzed using one-way Anova test. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated from logistic regression models. Results: There were 175 Chinese patients diagnosed with invasive breast cancers from 2005 to 2012. Median age at diagnosis was 54 (range 27-90). One hundred fourteen (65%) were HR+, 41 (23%) were HER2+, and 20 (11%) were TN. There were 59 (34%) patients diagnosed at age ≤ 50 and twelve patients (7%) were diagnosed at age < 40. There were more HER2+ and TN breast cancers diagnosed in women age ≤ 50 compared to age > 50, but the difference was not statistically significant. Women in the HR+ group were diagnosed at an older age compared to the other two subgroups (57 ± 12, 52 ± 8, and 52 ± 10 for HR+, HER2+, and TN, respectively, p = 0.036). Patients with TN breast cancers were more likely to have lymph node involvement compared to HR+ or HER2+ patients (p = 0.02). There was a trend of increasing prevalence of HER2+ breast cancer observed in recent years: 18.5% in 2005-2006, 23.8% in 2007-2008, 18.4% in 2009-2010, and 29.8% in 2011-2012. Conclusions: We observed a high proportion of breast cancer among young Chinese Americans as well as an increasing prevalence of HER2+ breast cancer in this population in recent years. Further studies are warranted.

Variability in metabolic cross-feeding behaviors in breast cancer and response to neoadjuvant chemotherapy.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e12645-e12645
Author(s):  
Joseph R Peterson ◽  
John A Cole ◽  
Tyler M Earnest ◽  
Micahel J Hallock ◽  
Tushar Pandey ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Density Lipoprotein ◽  
In Silico Analysis ◽  
Primary Energy ◽  
Intrinsic Subtype ◽  
Breast Cancers ◽  
Luminal A ◽  
Feeding Behaviors ◽  
Cancer Subtypes

e12645 Background: Success of neoadjuvant chemotherapy (NACT) varies by intrinsic subtype of a patient’s breast cancer (e.g., Normal-like, Luminal A/B, HER2-enriched, Triple Negative). The metabolic rate of a given tumor is implicated in response to chemotherapies, as many act by killing rapidly dividing cells. Metabolic dis-regulation opens avenues for cancer cells to exploit environmental niches arising in the tumor microenvironment (TME). Focusing on the role the TME plays in defining cancer behavior, we undertook a theoretical investigation to uncover how metabolic cross-feeding affects subtype behavior and patient response. Methods: An in silico analysis of cross-feeding variability arising from metabolic differences breast cancers was undertaken. TME community models consisting of fatty, glandular, and cancerous tissues’ metabolic behaviors were created. Expression levels of metabolic enzymes for 1222 community patients in TCGA BRCA were used to create models. Models were used in 3D simulations of tumors for 300 patients from the TCIA (Clark et al., J. Digital Imaging, 2013). Cross-feeding trends within each intrinsic subtype were analyzed. Results: Predicted TME metabolic capabilities were compared to literature: LA/LB had lower amino acid consumption than TNBC/HER2+ for asparagine, glutamine (Glu), tryptophan, phenylalanine (van Geldermolsen et al. Oncogone 2016; Furuya et al. Cancer Sci. 2012). Additionally, TNBC tumors produced Glu which was consumed by adipose tissue ( Cao et al. BMC Cancer, 2014), TNBC produced methionine and proline (Kanaan et al. Can. Gen. Prot. 2014), and TNBC/HER2+ cancers consumed high density lipoprotein produced by adipose (Balabum et al. Cancer Met. 2017). The simulations revealed novel cross-feeding behaviors. In general, TNBC/HER2+ relied on glucose as the primary energy source, while LA/LB relied on the amino acids alanine, glycine and Glu. TNBC/HER2+ cancers produced high levels of lactate which was consumed by adipose tissues. Uniquely, glycine produced by cancer was consumed by fat in TNBC cancers Several environmental niches were induced in the healthy tissue by the presence of the cancer; for example, ornithine was predicted to be cross-fed from fatty to glandular tissues in TNBC/HER2+ cancers, and glutamate and inosine from glandular to fatty tissues in HER2+ cancers. Conclusions: Metabolic niches provide opportunities for cancer subtypes. These results suggest that metabolic pathway usage can lead to difference in growth, cross-feeding, and drug efficacy.

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