Tagged: Breast Cancer

Defining the Complexity of EGFR Endocytosis in Cancer

April 27, 2023

In a new editorial perspective, researchers delve into the complex mechanisms underlying EGFR endocytosis and its potential as a therapeutic target.

Figure 1: SNX3 protein downregulation in breast tumors.

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EGFR (epidermal growth factor receptor) is a crucial protein that plays a significant role in various biological processes such as cell growth, proliferation, differentiation, and survival. Dysregulation of EGFR signaling has been implicated in the development and progression of numerous human cancers, including lung, breast and colon cancer. Therefore, EGFR has emerged as an attractive target for cancer therapy, and several drugs that target EGFR are in clinical use or under investigation.

In recent years, endocytosis, the process by which cells internalize molecules and transport them into intracellular compartments, has emerged as a critical modulator of EGFR signaling. Endocytosis of EGFR not only regulates the duration and intensity of EGFR signaling but also modulates the signaling output. Dysregulation of EGFR endocytosis has been implicated in the development of drug resistance to EGFR-targeted therapies, highlighting the importance of understanding the mechanisms that regulate EGFR endocytosis.

In a new editorial perspective, researchers Aysegul Sapmaz and Ayse Elif Erson-Bensan from Middle East Technical University provide an overview of the recent advances in our understanding of EGFR endocytosis and its role in EGFR signaling and cancer. The authors highlight the importance of the dynamic interplay between EGFR endocytosis and downstream signaling pathways and discuss how aberrant EGFR endocytosis contributes to drug resistance to EGFR-targeted therapies. On April 10, 2023, their editorial perspective was published in Oncotarget’s Volume 14, entitled, “EGFR endocytosis: more than meets the eye.”

“Here we review the role of the EGF-SNX3-EGFR axis in breast cancers with an extended discussion on deregulated EGFR endocytosis in cancer.”

EGFR Endocytosis

In a recent 2022 study, Sapmaz, Erson-Bensan and their team made significant contributions to understanding the role of deregulated endocytosis in cancer by describing the tumor suppressor role of Sorting Nexin 3 (SNX3) in triple-negative breast cancers (TNBCs). SNX3 is a protein-coding gene belonging to a family of proteins called sorting nexins, which are involved in sorting and trafficking of cellular membrane proteins and lipids. At the conclusion of their study, the researchers found that SNX3 is a critical player in TNBCs through the EGF-SNX3-EGFR axis.

“SNX3, an endosomal trafficking protein, is an emerging tumor suppressor in breast cancers as a target of the EGFactivated EGFR pathways and a modulator of EGFR protein levels.”

In the current editorial perspective by Sapmaz and Erson-Bensan, they discuss overexpression of EGFR and its activating mutations linked to various cancer phenotypes, including stemness, metastasis and drug resistance. Endocytosis and the internalization of EGFR play a crucial role in regulating its activity, which is dependent on post-translational modifications and regulated by various proteins, including ubiquitin. Deregulation of these players in endocytic processes has significant implications for EGFR activity in cancers. The ubiquitination status of EGFR and other proteins in the endocytic pathway is functionally essential and is balanced by E3 ubiquitin ligases and deubiquitinating enzymes (DUBs). Targeting these enzymes to alter ubiquitination dynamics could offer future perspectives in manipulating EGFR endocytosis and signaling in cancers.

The researchers discuss the non-canonical functions of endocytosis and endocytosis-related proteins, such as their involvement in nucleocytoplasmic shuttling and transcriptional activity. Several endocytic proteins have been found to interact with nuclear proteins and modulate gene transcription. Examples include EPS15, EPN1 and RNF11, which can shuttle between the cytoplasm and nucleus and have been shown to positively regulate transcription. Other endocytic proteins and adaptors have also been found to shuttle between the cytoplasm and nucleus with functions in endocytosis and gene expression. The authors emphasize the need for a better understanding of both the canonical and non-canonical functions of endocytic processes for normal physiology and diseases, including cancer and other pathologies.

“A better understanding of these backstage mechanisms will allow a more comprehensive understanding of receptor fate and activity.”

Conclusions

In conclusion, EGFR and its regulation through endocytosis have emerged as critical players in cancer development and progression. Dysregulation of EGFR endocytosis has been implicated in drug resistance to EGFR-targeted therapies, highlighting the importance of understanding the mechanisms that regulate this process. Recent advances in our understanding of EGFR endocytosis and its role in cancer have revealed the critical interplay between EGFR signaling and downstream pathways. The research by Sapmaz and Erson-Bensan sheds light on the tumor suppressor role of SNX3 in TNBCs and highlights the need for a better understanding of the canonical and non-canonical functions of endocytic processes in normal physiology and diseases, including cancer. Future research focusing on manipulating EGFR endocytosis and signaling could offer new perspectives on cancer therapy.

“Finally, before we can consider key endocytosis regulators as therapeutic targets, these candidate proteins must also be evaluated within the context of potential feedback mechanisms to modulate the biosynthesis and repopulation of receptors in cancer cells.”

Click here to read the full editorial perspective in Oncotarget.

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Researchers Identify New Drug Candidates to Treat DLST+ Tumors

January 19, 2023

The increased expression of DLST has recently been associated with increased tumor aggression and a poor prognosis in neuroblastoma and triple-negative breast cancer.

Figure 3: Analysis of DLST-activated cell lines revealed sensitivity to protein kinase inhibiting the ERK/MAPK pathway.

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Dihydrolipoamide S-succinyltransferase (DLST) is a crucial gene/protein/enzyme involved in the oxidative phosphorylation (OXPHOS) pathway and cellular energy production. Recent studies have demonstrated that, in neuroblastoma and triple-negative breast cancer (TNBC), increased expression of DLST is associated with increased tumor aggression and a poor disease prognosis. Researchers also found that, in leukemia and TNBC cell lines, the knockdown of DLST leads to apoptosis. These findings suggest that neuroblastoma and TNBC may benefit from DLST-inhibiting cancer therapy.

In light of this evidence, researchers Christina Kuhn, Myriam Boeschen, Manuel Philip, Torsten Schöneberg, Doreen Thor, and Susanne Horn from the University of Leipzig, University Duisburg-Essen and the German Cancer Consortium investigated approved drugs that may target DLST-activated tumors. In their recent study, the team used data from the Genomics of Drug Sensitivity in Cancer (GDSC) project to identify new drug candidates for the treatment of DLST-activated tumors. On January 12, 2023, their research paper was published in Oncotarget’s Volume 14, entitled, “Candidate drugs associated with sensitivity of cancer cell lines with DLST amplification or high mRNA levels.”

The Study

“With the advent of complex genetic datasets of roughly 1000 cell lines in the Cancer Cell Line Encyclopedia (CCLE) and on drug resistance in the Genomics of Drug Sensitivity in Cancer project (GDSC), analyses of drug sensitivity have become possible on a larger scale [6, 7].”

Since neuroblastoma and TNBC tumor cell viability may be DLST-dependent, DLST is a promising target for cancer therapy. The researchers used the Cancer Cell Line Encyclopedia (CCLE) to identify cancer cell lines with DLST amplifications or high mRNA levels. They then measured the sensitivity of these DLST+ cell lines to 250 drugs in the GDSC dataset and compared the data to a subset of cell lines without DLST amplifications or high mRNA levels.

“To identify drugs that inhibit viability of specifically DLST-activated tumor cells, we compared cell lines with supposedly activating changes of DLST (DNA amplification, high mRNA levels) to cell lines without DLST changes.”

Results & Conclusions

“DLST-altered cell lines were more sensitive to 7 approved drugs, among these obatoclax mesylate, a BCL2 inhibitor that reduces OXPHOS in human leukemia stem cells.”

The researchers identified seven drug candidates that demonstrated significantly higher sensitivity in DLST+ cell lines than in the control cell lines. In addition to a BCL2 inhibitor found to reduce OXPHOS, multiple protein kinase inhibitors were identified as efficient in the DLST+ cell lines. This suggests that DLST-altered cell lines may also be vulnerable to ERK/MAPK pathway-targeting drugs. The researchers propose that the drug candidates identified in this study warrant further drug efficacy testing in knock-in cell lines and DLST-activated tumors.

“We therefore conclude that, in addition to OXPHOS, protein kinases could be potential targets of therapy in the presence of DLST amplifications or high mRNA levels.”

Click here to read the full research paper published by Oncotarget.

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Oncotarget is an open-access, peer reviewed journal that has published primarily oncology-focused research papers since 2010. These papers are available to readers (at no cost and free of subscription barriers) in a continuous publishing format at Oncotarget.com. Oncotarget is indexed/archived on MEDLINE / PMC / PubMed.

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CRISPR Screens Identify Novel Targets for Personalized Cancer Therapy

October 7, 2022

In this trending new study, researchers used CRISPR-based genome-wide screens to identify genetic determinants of PARP10-mediated cellular survival.

CRISPR Screens Identify Novel Targets for Personalized Cancer Therapy

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Genetic interactions involved in the survival of cancer cells are potential therapeutic targets in personalized cancer therapy. “Synthetic lethal” is a type of genetic interaction where the knockout of one gene can cause cell death but only in the presence of another dependent gene. Cancer researchers view synthetic lethality screening as a powerful tool in precision medicine.

“Identifying genetic susceptibilities based on PARP10 expression levels is thus potentially relevant for finding new targets for precision oncology.”

Poly-ADP-ribose polymerase 10, or PARP10, is a nuclear protein that is overexpressed in multiple cancers. Genetic susceptibilities based on PARP10 expression levels in an individual may be potential targets for personalized cancer therapy. In a new study, researchers Jude B. Khatib, Emily M. Schleicher, Lindsey M. Jackson, Ashna Dhoonmoon, George-Lucian Moldovan, and Claudia M. Nicolae, from the Department of Biochemistry and Molecular Biology at Penn State College of Medicine, used CRISPR-based, genome-wide genetic screens to identify potential synthetic lethality interactions with PARP10-overexpressing and -knockout cancer cells. On September 28, 2022, their research paper was published in Oncotarget and entitled, “Complementary CRISPR genome-wide genetic screens in PARP10-knockout and overexpressing cells identify synthetic interactions for PARP10-mediated cellular survival.”

“Here, we employed complementary CRISPR loss-of-function genome-wide screening to identify genes required for proliferation of PARP10-overexpressing and PARP10-knockout cells.”

The Study

To identify potential synthetic lethal targets, the researchers conducted a CRISPR-based, genome-wide genetic screen of both PARP10-overexpressing and PARP10-knockout tumorigenic and non-tumorigenic breast cells. The screen looked for genes that were required for cell proliferation in the presence of PARP10 overexpression or PARP10 knockout.

“Here, we performed a series of CRISPR genome-wide loss-of-function screens in isogenic control and PARP10-overexpressing or PARP10-knockout cell lines, to identify genetic determinants of PARP10-mediated cellular survival.”

In the PARP10 overexpressing cells, the top results from their CRISPR screen were validated with biological pathway enrichment analyses, using both KEGG and Gene Ontology databases. A functional interaction between ATM and PARP10 expression was found. ATM promoted cell proliferation in PARP10-overexpressing cells.

In the genome-wide CRISPR knockout screens, genes required for the viability of PARP10-knockout cells were identified. In the PARP10 knockout cells, the top results from their CRISPR screen were validated with biological pathway enrichment analyses, using both KEGG and Gene Ontology databases. They identified the CDK2-Cyclin E1 complex as a genetic determinant for the proliferation of PARP10-knockout cells.

“Our work identifies a network of functionally relevant PARP10 synthetic interactions, and reveals a set of factors which can potentially be targeted in personalized cancer therapy.”

Conclusion

The researchers identified several genes that were differentially required for cell proliferation in the presence of PARP10 overexpression or knockout. Some of these genes have been previously implicated in cancer, while others were novel candidate cancer targets. The identification of these potential synthetic lethal interactions provides new insights into the role of PARP10 in cancer and may be useful for precision oncology. This study highlights the importance of using complementary CRISPR-based screens to identify potential cancer targets.

“We found that DNA repair factors, including ATM, a master regulator of the DNA damage checkpoint response, are specifically promoting the proliferation of PARP10-overexpressing cells. Moreover, we identified a role for PARP10 in regulating ATM recruitment to stressed replication forks. Finally, we found that the CDK2-cyclin E1 complex is specifically required for the proliferation of PARP10-deficient cells. Our work reveals novel PARP10 genetic interactions of functional relevance and identifies a set of factors which can potentially be targeted in personalized cancer therapy.”

Click here to read the full research paper published by Oncotarget.

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Trending With Impact: Genes Identified in Endocrine Therapy Resistance

April 15, 2022

Researchers studied the dynamic behavior of gene expression during the development of endocrine therapy resistance in breast cancer.

Figure 4: Tissue-specific protein-protein interaction network for modules 1 and 2 candidate genes.

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Hormones can cause tumor growth in some subtypes of breast cancer. Endocrine therapy, also known as hormone therapy, is a type of cancer treatment that removes or blocks the hormones which fuel breast cancer growth. This treatment is often given as adjuvant therapy after breast cancer surgery to lower the risk of cancer reoccurrence. In some cases, endocrine therapy may be used as a first-line treatment for hormone receptor-positive breast cancers, such as estrogen receptor-positive (ER-positive) breast cancer. However, ER-positive tumors frequently become unresponsive to endocrine therapy, and tumor regrowth can occur after treatment. The underlying causes of endocrine resistance are mostly undetermined.

“Endocrine therapies have been successful at improving cancer outcomes; however, the development of endocrine resistance, or resistance to inhibition of ER actions, remains a roadblock in breast cancer treatment.”

Recently, researchers—from UTHealth Houston, University of Chicago, University of Texas MD Anderson Cancer Center, and the University of Houston—used a new statistical and computational pipeline method of analysis to study the dynamic behavior of gene expression during the development of endocrine resistance in breast cancer. Their trending research paper published in Oncotarget on April 06, 2022, is entitled, “A novel group of genes that cause endocrine resistance in breast cancer identified by dynamic gene expression analysis.”

The Pipeline

“In this study, we explored the dynamic behavior of the entire gene population to identify novel genes that play fundamental roles in the development and progression of endocrine-resistant breast cancer.”

Pipeline analysis in biology is a method of studying and analyzing a group of genes or proteins in order to understand their structure and function. The pipeline can be used to determine gene dynamics, clusters, similarities, and networks. In this case, the researchers used it to understand how endocrine resistance develops over time.

“The pipeline provides three main functions. First, statistical hypothesis testing determines a set of dynamic response genes (DRGs) that exhibit signiﬁcant changes over time. Next, these DRGs are clustered into gene response modules (GRMs), sets of DRGs with similar time course expression patterns. Finally, the GRMs associations and regulatory effect are analyzed as a gene regulatory network using ordinary differential equations.”

The Study

To begin this study, the researchers first aimed to select a cell-based model that represents endocrine resistance in patients as closely as possible. They gathered data from breast cancer patients who were either resistant or sensitive to endocrine therapies and compared them with publicly available gene expression data. Results showed that the LTED MCF7 cell model displayed similar endocrine resistance to patient tumor data.

Next, the researchers observed the development of endocrine therapy resistance in the LTED MCF7 cell model, as well as the changes in gene expression over time. This data was collected and used to develop a mathematical model of gene expression dynamics during endocrine therapy resistance development. After statistical and computational pipeline analysis, the team identified a group of 254 genes whose time course expression significantly changed during the development of endocrine therapy resistance. They then aimed to validate their findings and used multiple bioinformatics approaches to narrow down this group of candidate genes.

“To further refine the genes common to endocrine resistance development and progression, we utilized several bioinformatic approaches designated to rank and prioritize the 254 common genes.”

The Results

Candidate genes were narrowed down to a novel group of 34 genes whose time course expression most significantly changed during LTED MCF7 cell modeling of endocrine-resistant breast cancer development. In addition, microarray analysis also showed that a subset of these genes was differentially expressed in triple-negative breast cancer (TNBC). This suggests that there may be shared genetic mechanisms between endocrine-resistant breast cancer and TNBC.

“As these two subtypes of breast cancer are the most fatal breast cancers with no known effective therapeutic approaches available to date, research on underlying genetic factors is of great importance.”

Conclusion

Their analysis led to the identification of a novel group of 34 genes that may play a role in endocrine resistance. Interestingly, some of these genes were also differentially expressed in TNBC. These findings could potentially lead to the development of new therapeutic strategies to overcome endocrine therapy resistance in some of the most difficult to treat and fatal breast cancers.

“Our analysis identified novel candidate genes with potential significance in endocrine-resistant breast cancer as well as TNBC, which opens new doors for designing novel therapeutic approaches for endocrine-resistant breast cancer and TNBC.”

Click here to read the full research paper published by Oncotarget.

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A Remote Weight Loss Strategy for Breast Cancer Survivors

March 9, 2022

Researchers Jennifer Y. Sheng and Vered Stearns discussed the results of a study that compared weight loss interventions among overweight or obese survivors of breast cancer.

Weight loss for survivors of breast cancer

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After being diagnosed with breast cancer, up to 96% of women have reported gaining weight. Medications, inactivity, food choice, and food quantity can all lead to weight gain. Studies have shown that weight gain can increase the risk of breast cancer recurrence by 40–50% and breast cancer-related mortality by 53–60%. Thus, for women with breast cancer and those who have survived breast cancer, weight management is a potentially life-saving intervention.

In an editorial paper published by Oncotarget in 2021, researchers Jennifer Y. Sheng and Vered Stearns from Johns Hopkins School of Medicine and the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center discussed the results of the 2020 POWER-Remote Trial—a study among breast cancer survivors on the results of a remote-based weight loss program compared with a self-directed approach. Their editorial paper is entitled, “Innovating and expanding weight loss strategies for breast cancer survivors.”

The POWER Intervention

The Practice-based Opportunities for Weight Reduction (POWER) intervention is a 12-week behavioral weight loss program designed for overweight and obese participants. The POWER program strategy focuses on physical activity and behavioral changes, nutrition education and setting individual goals. Researchers developed the POWER-remote intervention to enable participants to engage in this weight loss program remotely through weekly video conferences and phone calls. In the current editorial paper, the researchers discussed the results from a study that adapted the POWER-remote intervention for breast cancer survivors: the POWER-Remote Trial.

“The original Practice-based Opportunities for Weight Reduction (POWER) study in obese individuals with a risk for cardiovascular disease demonstrated equivalent weight loss outcomes between in-person coaching and a remote intervention [24].”

The POWER-Remote Trial

The POWER-Remote Trial was a randomized, controlled comparative effectiveness trial that evaluated the POWER-remote intervention compared to a self-directed weight loss approach among overweight or obese breast cancer survivors. Between 2013 and 2015, 87 overweight or obese women with stage 0-III breast cancer (who completed local therapy and chemotherapy) were evaluable for analysis in this study. Forty-five women were enrolled in the POWER-remote arm of the study and 42 women were enrolled in the self-directed arm.

“Our group compared the remote-based POWER intervention (telephone calls by a coach, access to online learning materials, online self-directed dietary/activity monitoring) to self-directed weight loss in overweight or obese survivors of early-stage breast cancer [25].”

Over the course of the study, the researchers found high adherence in the POWER-remote arm, with only one participant lost in follow-up. At the 12-month mark, 51% of the POWER-remote participants lost greater than or equal to 5% of their baseline body weight. Among the self-directed participants, 17% lost 5% or more of their baseline body weight. The results of this study suggest that the POWER-remote intervention is an effective weight loss strategy. It is a cost-effective, scalable and conscientious solution to assist with weight loss among many breast cancer survivors.

Conclusion

Despite the significant improvements in weight, body composition, fitness, and quality of life seen by over half of the participants in the POWER-remote arm, the researchers also pointed out a problem. The POWER-remote intervention still did not yield significant results in almost half of the other participants. Trouble sleeping was shown as a potential culprit that hindered weight loss, while many other factors inhibiting weight loss in this population are not yet fully understood.

The authors wrote that it may be necessary to further individualize or enhance the POWER intervention to achieve greater success in breast cancer survivors. They also suggested that, in some people, the POWER program may need to be augmented with pharmacological agents to aid in weight loss. In addition, the authors believe that the payer system should be reevaluated to expand coverage for obesity treatments.

“At present, I’m conducting a phase two study to determine whether an adaptor approach with pharmacotherapy can augment obesity treatment in breast cancer survivors. This study is called the A-NEW study, which stands for an Adaptive Nutrition and Exercise Weight Loss Study,” Dr. Jennifer Sheng said in a recent Behind the Study interview with Oncotarget. “We’re also looking forward to analyzing results from the COOIN study, the Cancer, Obesity, Overweight, and Insomnia study, which was led by Dr. Janelle Coughlin.”

Author Interview: Dr. Sheng discusses the research behind the editorial
Author Testimonial: Dr. Sheng describes the experience publishing with Oncotarget
Behind the Study: Transcription of Dr. Sheng’s research discussion

Click here to read the full editorial paper published by Oncotarget.

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Trending With Impact: Are NOTCH1 Variants Prognostic in Breast Cancer?

February 24, 2022

Researchers determined the prognostic ability of three NOTCH1 gene variants by incorporating them into two non-tumorigenic breast cell lines.

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The genetic changes that occur within the protein-coding gene NOTCH1 have not yet been fully studied or classified. Despite a lack in research, previous studies have suggested that NOTCH1 may be a potential target for novel cancer therapies, particularly against triple-negative breast cancer (TNBC). NOTCH1 variants in TNBC tend to cluster in the PEST region and have previously been linked to gamma secretase inhibitor (GSI) sensitivity and chemotherapy resistance.

“Furthermore, TNBC patients with increased Notch1 expression have demonstrated increased aggressive phenotypes and lower median overall survival [25].”

Since TNBC is well-known for a lack of actionable therapeutic targets, aggressive phenotypes and poor prognoses, there is an important need to develop new targeted therapies—as well as predictive markers for those therapies. Researchers from The Johns Hopkins University School of Medicine, Vanderbilt University Medical Center and The Vanderbilt-Ingram Cancer Center experimented in vitro with NOTCH1 variants and their ability to predict TNBC responsiveness to GSIs and standard of care chemotherapies. Their trending research paper was published by Oncotarget on February 16, 2022, and entitled, “NOTCH1 PEST domain variants are responsive to standard of care treatments despite distinct transformative properties in a breast cancer model.”

The Study

The researchers used three publicly available tumor-associated variant databases to identify three NOTCH1 variants that are commonly mutated in breast cancers; two variants were located in the A2441 site on NOTCH1 and the third variant was located in the PEST region of NOTCH1. To investigate the role of these NOTCH1 variants in TNBC in vitro, the team cultured two non-tumorigenic breast epithelial cell lines. Uniquely, they used an adeno-associated virus (AAV) vector to isogenically incorporate the NOTCH1 variants into the two cell lines. The researchers also developed a wildtype vector for the control arm of the study.

“In addition to the NOTCH1 variants, a targeted wildtype (TWT), which underwent the same gene targeting mechanism with a wildtype vector, was generated for both parental cell lines to act as a control.”

A standard growth factor supplemented media was used to determine if the NOTCH1 variants caused increased proliferation in the non-tumorigenic cell lines. Compared to the controls, no significant change in proliferation was observed. They also removed the epidermal growth factor (EGF) from the cells to determine if these NOTCH1 variants impart a ligand-independent proliferative advantage. In both cell lines, their results demonstrated that the A2441 variants exhibited EGF-independent growth, while the PEST NOTCH1 variant did not. Immunoblot analyses suggested that, in the absence of EGF, the A2441 NOTCH1 variants activated the MAPK pathway. These EGF-independent NOTCH1 variants (not the PEST NOTCH1 variant) conferred an invasive growth phenotype, increased migratory potential, had dysregulated 3D morphology, and significantly altered gene expression in cancer pathway genes.

Next, to measure the responsiveness and susceptibility of these variants to therapeutic agents, the cells were treated with six chemotherapeutic agents and nirogacestat—a GSI drug. Interestingly, none of the three variants demonstrated significantly different responses to the treatments when compared to one another. Furthermore, all of the variants showed sensitivity to these standard therapies used against TNBC. This suggests that these specific genetic changes within NOTCH do not have a large impact on tumor behavior and may not be useful as predictive markers for therapy response.

Conclusion

“Taken together, these data suggest that the oncogenic potential of NOTCH1 PEST domain variants depends on both variant type and amino acid location.”

Contrary to previous studies, the researchers found that the three NOTCH variants did not demonstrate significantly different responses to the GSI or the chemotherapies despite demonstrating distinct phenotypes. The lack of differential responses demonstrated by the variants in this study suggests that there is high variability among NOTCH1 variants. The prognostic potential of NOTCH1 may be dependent on the type of variant and its location, but more expansive research is necessary.

“Future studies involving meticulous characterization of an expansive panel of NOTCH1 variants in a similar model may provide mechanistic insight and predictive and/or prognostic value that is both variant type and site dependent.”

Click here to read the full research paper published by Oncotarget.

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Chemical in Sunscreen Promotes Breast Cancer in Diet-Dependent Manner

November 18, 2021

The bioactivity of oxybenzone—a harmful chemical often found in sunscreens—was examined within mouse models of breast cancer in high- and low-fat dietary contexts.

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Oxybenzone (benzophenone-3; BP-3) is a toxic endocrine-disrupting chemical (EDC). Alarmingly, this chemical has been identified as a common ingredient in some brands of sunscreen. Oxybenzone can often be found in humans, household dust, fish and, due to its widespread human use, the water environment—causing harm to coral reefs and other murine life. Previous studies have shown that environmental toxins and estrogenic chemicals have emerged as potential culprits in the promotion of breast cancer. Furthermore, oxybenzone has been known to have estrogenic and anti-estrogenic properties.

“Although BP-3 has a very short half-life, its presence is widespread in human urine [9], in as much as 98% of the general U.S. population [13].”

Researchers from the Breast Cancer and the Environment Research Program at Michigan State University studied the diet-dependent effects of oxybenzone in mouse models of mammary tumorigenesis during puberty and adulthood. Their paper was published by Oncotarget in 2020, and entitled, “Benzophenone-3 promotion of mammary tumorigenesis is diet-dependent.”

“We [previously] demonstrated enhancement of mammary tumorigenesis by a diet high in saturated animal fat (HFD) [5–8]. Thus, examination of the activity of EDCs in a dietary context may provide additional insight into the potential role of EDCs in promoting breast cancer.”

The Study

In the current study, the team employed the Trp53–null transplantation of a basal-like breast cancer mouse model. The researchers previously demonstrated that proliferative, inflammatory and angiogenic activity in the mammary gland can be modulated by estrogen and a high-fat diet (HFD). Therefore, both pubertal and adult mice were placed on either low- or high-fat diets. After one week, study mice were ovariectomized, given time for recovery and the natural dissipation of endogenous hormones, and then treated for five days with either saline (control) or 17β-estradiol (E2).

Next, the estrogenic or anti-estrogenic effects of oxybenzone were examined in these mice under three dietary conditions: mice fed a life-long low-fat diet (LFD), mice fed a LFD during puberty and then a HFD in adulthood (LFD-HFD) and finally, mice fed a HFD during puberty and then a LFD in adulthood (HFD-LFD). Mice in LFD-HFD and HFD-LFD groups were fed their initial diet from three to 10 weeks of age, and were then switched to the alternative diet. Half of these mice were injected with oxybenzone and the other half (control) were injected with saline.

“We found that BP-3 had complex effects that were dependent upon dietary regimen and tumor histopathology.”

Results

Consistent with their previous studies, the researchers found that most of the tumors developed were epithelial in histological composition, and few were spindle cell carcinomas. They found that oxybenzone reduced the tumorigenesis of epithelial tumors in LFD mice. The LFD-HFD combination resulted in more spindle cell tumors compared to the life-long LFD mice. Oxybenzone treatment increased the tumorigenesis of epithelial tumors in mice fed the LFD-HFD.

“Kaplan-Meier analysis revealed that BP-3 reduced tumorigenesis of epithelial tumors in mice fed LFD (Figure 3A). On the other hand, consistent with the increased proportion of epithelial tumors, BP-3 was promotional for epithelial tumorigenesis in mice fed LFD-HFD (Figure 3C), while reducing spindle cell tumorigenesis (Figure 3D).”

Researchers saw that proliferation was increased by oxybenzone treatment most significantly in the mammary glands of 26-week-old HFD mice. Curiously, oxybenzone treatment increased the number of lesions only in mice fed the HFD-LFD. The researchers note that, in this study and others, a “pubertal window of susceptibility” was observed, reinforcing the important notion that puberty is a highly sensitive window of time for poor diets and adverse exposures to environmental toxins. Ultimately, the team found that oxybenzone enhances estrogen-stimulated breast cancer cell proliferation in pubertal mice fed a HFD.

“Benzophenone-3 increased tumor cell proliferation, decreased tumor cell apoptosis, and increased tumor vascularity dependent on specific dietary regimen and tumor histopathology.”

Conclusion

Collectively, the researchers’ findings suggest that exposure to oxybenzone has adverse consequences in mammary tumorigenesis. The degree of severity appeared to be modulated differently among the three dietary regimens studied. Mice fed a HFD in adulthood experienced a decrease in tumor cell apoptosis and an increase in tumor vascularity and tumor cell proliferation. They note that there is future value in exploring the differences between pubertal and adult exposure to oxybenzone on a constant diet regimen.

“This points to a need for further studies of benzophenone-3 in both animal models and humans as a potential breast cancer risk factor, as well as a more general need to evaluate endocrine disrupting chemicals in varying dietary contexts.”

Click here to read the full scientific study, published by Oncotarget.

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Oncotarget

New Study: Vaccine Enhances Breast Cancer Treatment

October 27, 2021

Researchers conducted a study to examine the efficacy of adding the P10s-PADRE vaccine to chemotherapy treatments for patients with HR+/HER2− breast cancer.

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The most common type of breast cancer in the United States is HR+/HER2− breast cancer. Patients with HR+/HER2− breast cancer often face the threat of distant recurrence—long after the completion of their treatment. Previous studies have found that high levels of tumor infiltrating lymphocytes (TILs) were associated with improved outcomes and recurrence-free survival in patients with HR+/HER2− breast cancer. These studies and many others have prompted researchers to further develop and test cancer vaccinesin an effort to elicit anti-tumor immune responses in these patients.

“Therefore, a rational combination therapy that enhances the immune-stimulatory properties of NAC [neoadjuvant chemotherapy], can provide long-term survival benefits for this patient population.”

Researchers from University of Arkansas for Medical Sciences, University of Texas Southwestern, Highlands Oncology Group, and Université Claude Bernard Lyon 1 conducted a new single-arm Phase Ib clinical trial. Early-stage HR+/HER2− breast cancer patients were treated with carbohydrate-mimetic peptides, the P10s-PADRE vaccine, in combination with chemotherapy treatments. Their paper was chosen as the cover of Oncotarget’s Volume 12, Issue 22, and entitled, “P10s-PADRE vaccine combined with neoadjuvant chemotherapy in ER-positive breast cancer patients induces humoral and cellular immune responses.”

“The main objective of our study was to determine an appropriate schedule to be used for adding the P10s-PADRE vaccine to cancer chemotherapy in the neoadjuvant setting considering the ability of the vaccine to elicit adequate antibody response.”

The Study

After meeting the study’s detailed inclusion/exclusion criteria, a total of 25 patients with HR+/HER2− breast cancer were selected to partake in this single-arm Phase Ib clinical trial. Patients were divided into five cohorts (five patients per cohort): A, B, C, D, and E. Each patient was treated with a combination of four therapies over the course of 22-25 weeks, including three doses of thepeptide-based P10s-PADRE cancer vaccine, four doses of Cyclophosphamide (chemotherapy), four doses of Doxorubicin (chemotherapy) and four doses of Docetaxel (chemotherapy). Using a cohort-specific treatment schedule for the previously stated combination of therapies, the researchers assessed the feasibility, safety and immunogenicity achieved in each cohort and each patient.

Additionally, patients underwent surgery between weeks 26 and 33 (four to eight weeks after their last chemotherapy treatment). Each cohort also had a cohort-specific blood draw schedule—blood was drawn at eight different times in the 73-week time frame. Blood draws were used to conduct flow cytometry, measure the concentration of cytokines, natural killer (NK) cells and antibodies, and to determine the presence of anti-peptide antibody response and the percentage of TILs. The researchers observed that all five cohorts saw a significant reduction in tumor size.

“The data suggest that subjects enrolled in schedule C generated a more consistent and robust antibody response, therefore schedule C appears as the schedule of choice for future combination therapy.”

Their findings concluded that, in combination with chemotherapy, P10s-PADRE immunization in HR+/HER2− breast cancer patients induced “acceptable” antibody responses in study cohorts C and E. The treatment schedule in cohort C demonstrated the strongest antibody response by affecting the expression levels of NK-cell markers, stimulating the production of cytokines, T-cells and TILs. However, the researchers note that continued analysis of the blood samples collected could show serum antibodies may begin to appear later on in patients enrolled in the other treatment schedules.

Conclusion

“This Phase Ib clinical trial of the P10s-PADRE vaccine shows that immunization in combination with a standard-of-care NAC is feasible and well-tolerated. Combination therapy induces antibody response, stimulates activation of NK cells, and is associated with infiltration of T cells in tumor microenvironment. Randomized phase II trials focusing on treatment schedule C are needed to validate current findings and evaluate clinical efficacy.”

Click here to read the full research paper, published by Oncotarget.

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Oncotarget

Trending With Impact: Analysis of Breast Cancer in Nigerian Women

August 16, 2021

In this trending paper published by Oncotarget in 2021, a cohort of Nigerian women were assessed for a useful biomarker in aggressive molecular subtypes of breast cancer.

The Trending with Impact series highlights Oncotarget publications attracting higher visibility among readers around the world online, in the news, and on social media—beyond normal readership levels. Look for future science news about the latest trending publications here, and at Oncotarget.com.

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Forms of cancer can vary in prevalence and aggression in different populations of people around the world. For instance, incidence rates of breast cancer (BC) have been rising in Africa over the past few decades. Research finds that Nigerian women have the highest age-standardized mortality rate of breast cancer on the African continent. This population in particular also faces disproportionately aggressive molecular subtypes of breast cancer.

“BC in Nigeria is characterized by disproportionately aggressive molecular subtypes, with exceptionally high rates of triple-negative (TN) BC [4], similar to BC in other countries in West Africa [5] and among African American women in the United States [6].”

In order to develop better treatment strategies, there is a distinct need to identify biomarkers that indicate, and even predict, these aggressive subtypes of breast cancer in Nigerian women. In 2021, a new study was conducted by researchers from Duke University, University of Lagos, Obafemi Awolowo University Teaching Hospital, University of Ibadan, Federal Medical Center Abeokuta, UNC Gillings School of Global Public Health, Our Lady of Apostle Catholic Hospital in Ibadan, University of Alabama at Birmingham, University of Kentucky, and University of Kansas Medical Center. Their trending research paper was published by Oncotarget and entitled, “Association of high-sensitivity C-reactive protein and odds of breast cancer by molecular subtype: analysis of the MEND study.”

C-Reactive Protein

“C-reactive protein (CRP) is associated with risk and aggressiveness for several types of cancer.”

When there is inflammation in the body, levels of the C-reactive protein (CRP) increase. This easily measurable protein can be a useful biomarker of systemic inflammation, infection, or tissue damage. Previous studies show that circulating CRP has been elevated in various types of cancers; it has also been associated with tumor prognosis. Past studies about CRP’s association in breast cancer subtypes have been notably few, and none have focused on isolating subpopulations in Africa.

“Additionally, it is worth noting that most of these past studies have been conducted in populations from the United States and Europe, among mostly White study populations, and to our knowledge, none have been conducted in populations from Africa.”

The Study

In this study, 555 Nigerian participants were assembled—of which 296 were confirmed breast cancer cases, and 259 were controls. The researchers collected clinical and reproductive characteristics of each participant, including the controls. In their first analysis, the researchers observed that newly diagnosed cases of Nigerian breast cancer were significantly more likely to have high levels of highly-sensitive CRP (hsCRP) compared to the controls. After adjusting for socio-demographic, clinical, and reproductive variables, the team still observed significant statistical significance for high levels of hsCRP associated with Nigerian BC. The findings from this cohort study also showed that high hsCRP was associated with a four-fold increased odds of BC.

“We also provide novel evidence of associations between hsCRP and BC molecular subtypes, with significant associations observed for luminal A, TN, and HER-enriched subtypes.”

Conclusion

“In conclusion, our analysis revealed a positive association between hsCRP and odds of BC, overall and for all molecular subtypes. Because CRP is an easily measured biomarker in the blood, it may represent a useful predictor of BC in the Nigerian context. We urge larger studies, preferably prospective cohort studies, among women of African descent to further characterize this association.”

Click here to read the full research paper, published by Oncotarget.

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Oncotarget

Trending With Impact: ONC201 Induces Apoptosis in Breast Cancer

July 1, 2021

A novel therapeutic combination converts anti-proliferative effects in breast cancer cells to pro-apoptotic.

Trending With Impact: ONC201 Induces Apoptosis in Breast Cancer — 3D illustration of the stages of cell apoptosis.

The Trending with Impact series highlights Oncotarget publications attracting higher visibility among readers around the world online, in the news, and on social media—beyond normal readership levels. Look for future science news about the latest trending publications here, and at Oncotarget.com.

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In the 1990s, Dr. Wafik El-Deiry’s cancer research laboratory discovered a gene that encodes a protein, called death receptor 5, or TRAIL receptor 2. TRAIL is a protein that induces the process of cell death, or apoptosis. This pathway activates the body’s innate immune system and is capable of suppressing cancer cells by inducing apoptosis.

After this discovery, researchers from the same lab considered the notion that increasing the production of TRAIL to enhance the body’s own immune response may have a safe therapeutic benefit in the treatment of cancer. The team searched for small molecules capable of upregulating the TRAIL gene and discovered the therapeutic compound TIC10, also known as ONC201. ONC201 is a well-tolerated drug currently being evaluated in advanced clinical trials for the treatment of various malignant solid tumors, including refractory metastatic breast cancer.

Researchers in Dr. El-Deiry’s laboratory have continued to investigate this drug in order to learn more about how it works, and what tactics or combinations may be used to produce better results for cancer patients. In a 2016 study, the researchers learned that ONC201 produces heterogeneous results in different tumor types.

“The question is, with this specific drug, what is the pattern of response, what determines that, and how can we get it to work a little bit better,” Dr. El-Deiry said in a recent Oncotarget interview.

Based out of Temple University, Fox Chase Cancer Center, Brown University, and the El-Deiry Cancer Research Laboratory, researchers wrote a paper detailing their latest study on ONC201. The paper was published by Oncotarget in 2020 and entitled, “TRAIL receptor agonists convert the response of breast cancer cells to ONC201 from anti-proliferative to apoptotic.”

THE STUDY

Led by first-author Dr. Marie Ralff, the researchers in this study found that ONC201 induces differential responses across various breast cancer tumor subtypes. Few breast cancers are responsive to TRAIL, and one subtype that is responsive to TRAIL is triple-negative breast cancer.

“We saw that in some of these tumor types (the triple-negative breast cancer type in particular) the compound was having a pro-apoptotic effect, and in other [breast cancer] tumor types, it was having an anti-proliferative effect,” said Dr. Ralff.

When comparing in vivo and in vitro results of the drug, the team found that the pro-apoptotic effects translated to efficacy, while the anti-proliferative effects did not. The researchers then decided to investigate strategies to convert breast cancer cell response to ONC201 from anti-proliferative to apoptotic. ONC201 affects two known mechanisms of TRAIL resistance in breast cancer: death receptor 5 and anti-apoptotic proteins. This fact led the researchers to introduce a TRAIL receptor agonist antibody in combination with ONC201.

“If we pretreat TRAIL resistant breast cancer cells with ONC201, the level of surface death receptor 5 goes up and the intracellular levels of anti-apoptotic proteins go down, thereby priming the cells to undergo death through the TRAIL pathway. So, if we then add in a TRAIL receptor agonist, it induces apoptosis in a very potent way,” Dr. Ralff said.

CONCLUSION

“The concept is when cells are treated with the small molecule compound, not a whole lot happens. When cells are treated with TRAIL, not a whole lot happens. When you put them together, it’s like flipping a switch. The cells now undergo potent cell death,” Dr. El-Deiry said.

The potential efficacy of this therapeutic combination was strengthened by results in the study showing that ONC201 paired with the TRAIL receptor agonist antibodies is non-toxic to fibroblasts. The researchers also showed that the natural killer cells are only active against the breast cancer cells that have been exposed to ONC201. In vivo studies reaffirmed the safety of this combination in mouse models.

Click here to read the full research study, published by Oncotarget.

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