Breast Cancer Therapeutics Research Articles

Identification of SLC31A1 as a prognostic biomarker and a target for therapeutics in breast cancer

Copper-induced cell death is regulated through protein lipoylation, which is critical for gene expression and phenotypic regulation. Neverless, the role of Cuproptosis-related genes in breast cancer (BC) remains unknown. This study aimed to construct a prognostic signature based on the expression of Cuproptosis-related genes in order to guide the diagnosis and treatment for BC. Cuproptosis-related genes prognostic signature has ata of 1250 BC tissues and 583 normal breast tissues were obtained from The Cancer Genome Atlas (TCGA), Genotype Tissue Expression (GTEx), and GEO GSE65212. The prognostic signature was established and evaluated with nineteen Cuproptosis-related genes. A series of in silico analyses based on SLC31A1, included expression analysis, independent prognostic analysis, correlation analysis, immune-related analysis and survival analysis. Finally, a series of cell experiments (including quantitative real-time polymerase chain reaction and western blot), and mice experiments were applied to evaluate the impact of SLC31A1 on BC. Cuproptosis-related genes prognostic signature has good predictive promising for survival in BC patients. We discovered that SLC31A1SLC31A1 was overexpressed in BC and was its independent prognostic factor. High expression of the SLC31A1 was correlated with poor prognosis and immune infiltrating of BC. SLC31A1 expression is associated with immune, chemotherapeutic and targeted therapy outcomes in BC. The proliferation, migration, and invasiveness of Her2 + enriched BC cells were decreased by SLC31A1 knockdown, also resulting in a decrease in tumor volume in mouse model. SLC31A1 is a candidate biomarker or therapeutic target in precision oncology, with diagnostic and prognostic significance in BC.

Virtual screening, molecular dynamics simulations, and in vitro validation of EGFR inhibitors as breast cancer therapeutics

A high abundance of Epidermal Growth Factor Receptor (EGFR) in malignant cells makes them a prospective therapeutic target for basal breast tumors. Although EGFR inhibitors are in development as anticancer therapeutics, there exists limitations due to the dose-limiting cytotoxicity that limits their clinical utilization, thereby necessitating the advancement of effective inhibitors. In the present study, we have developed common pharmacophore hypotheses using 30 known EGFR inhibitors. The best pharmacophore hypothesis DHRRR_1 was utilized for virtual screening (VS) of the Phase database containing 4.3 × 106 fully prepared compounds. The top 1000 hits were further subjected to ADME filtration followed by structure-based VS and Molecular Dynamics (MD) simulation investigations. Based on pharmacophore hypothesis matching, XP glide score, interactions between ligands and active site residues, ADME properties, and MD simulations, the five best hits (SN-01 through SN-05) were preferred for in-vitro cytotoxicity studies. All the molecules except SN-02 exhibited cytotoxicity in Triple Negative Breast Cancer (TNBC) cells. These potential EGFR inhibitors effectively downregulated the EGF-induced proliferation, migration, in-vitro tumorigenic capability, and EGFR activation (pEGFR) in the TNBCs. Additionally, in combination with doxorubicin, the identified EGFR inhibitors significantly decreased the EGF-induced proliferation. SN-04, and SN-05 in the presence of a lower concentration of doxorubicin markedly increased the apoptotic markers expression in the TNBCs, an effect which was comparable to a higher concentration of doxorubicin treatment, alone. These observations suggest that both SN-04 and/or SN-05 can improve the efficacy of chemotherapeutic drug, doxorubicin at a lower concentration to avert the higher dose of chemotherapeutic-induced side effects during breast cancer treatment.

Peptidomics and Machine Learning–based Evaluation of Noncoding RNA–Derived Micropeptides in Breast Cancer: Expression Patterns and Functional/Therapeutic Insights

Breast cancer is a highly heterogeneous disease characterized by different subtypes arising from molecular alterations that give the disease different phenotypes, clinical behaviors, and prognostic. The noncoding RNA (ncRNA)–derived micropeptides (MPs) represent a novel layer of complexity in cancer study once they can be biologically active and can present potential as biomarkers and also in therapeutics. However, few large-scale studies address the expression of these peptides at the peptidomics level or evaluate their functions and potential in peptide-based therapeutics for breast cancer. In this study, we propose deepening the landscape of ncRNA-derived MPs in breast cancer subtypes and advance the comprehension of the relevance of these molecules to the disease. First, we constructed a 16,349 unique putative MP sequence data set by integrating 2 previously published lists of predicted ncRNA-derived MPs. We evaluated its expression on high-throughput mass spectrometry data of breast tumor samples from different subtypes. Next, we applied several machine and deep learning tools, such as AntiCP 2.0, MULocDeep, PEPstrMOD, Peptipedia, and PreAIP, to predict its functions, cellular localization, tertiary structure, physicochemical features, and other properties related to therapeutics. We identified 58 peptides expressed on breast tissue, including 27 differentially expressed MPs in tumor compared with nontumor samples and MPs exhibiting tumor or subtype specificity. These peptides presented physicochemical features compatible with the canonical proteome and were predicted to influence the tumor immune environment and participate in cell communication, metabolism, and signaling processes. In addition, some MPs presented potential as anticancer, antiinflammatory, and antiangiogenic molecules. Our data demonstrate that MPs derived from ncRNAs have expression patterns associated with specific breast cancer subtypes and tumor specificity, thus highlighting their potential as biomarkers for molecular classification. We also reinforce the relevance of MPs as biologically active molecules that play a role in breast tumorigenesis, besides their potential in peptide-based therapeutics.

ADAR1 and ZBP1 in Breast Cancer: Pathological Mechanism and Therapeutics

Breast cancer is a heterogeneous disease in which a variety of genetic and environmental factors are involved. Among them, adenosine deaminase acting on RNA 1 (ADAR1) and Z-DNA binding protein 1 (ZBP1) are the factors that have opposite functions in the process of regulating cell viability as well as inflammatory and immunity. Recently, the two factors have been proved to act as a key player in caspase-8-dependent PANotosis and IFN-γ-dependent immunoregulation in the development of most types of cancers. In this review, we discuss the basic functions of ADAR1 and ZBP1 as well as the interactions between them in regulating innate immune responses in breast cancer therapeutics.

Targeting TRIM26: Unveiling an Oncogene and Identification of Plant Metabolites as a Potential Therapeutics for Breast Cancer.

Breast cancer is the major cause of cancer-related mortality and frequent malignancies among women worldwide. The TRIM (Tripartite Motif) protein family is a broad and diverse set of proteins that contain a conserved structural motif known as the tripartite motif, which comprises of three different domains, B-box domain, Coiled-coil domain and RBR (Ring-finger, B-box, and coiled-coil) domain. TRIM proteins are involved in regulating cancer growth and metastasis. However, TRIM proteins are still unexplored in cancer cell regulation. In this study, by using a cancer database expression of all TRIM proteins was determined in breast cancer. Out of 77 TRIM genes, 16 genes were upregulated in breast cancer. Here, the upregulated TRIM26 gene's role is not yet explored in breast cancer. Indeed, TRIM26 is upregulated in 21 cancer types out of 33 cancer types. To investigate the role of TRIM26 in breast cancer, siRNA-mediated gene silencing was carried out in MCF-7 and MDA-MB 231 breast cancer cells. Reduced expression of TRIM 26 decreased cancer cell proliferation, migration and invasion with simultaneous reduction of various proliferative, cell cycle and mesenchymal markers and upregulation of epithelial markers. Further, docking studies found potential novel plant metabolites. Thus, targeting TRIM26 may provide a novel therapeutic approach for breast cancer treatment.

Phytochemicals and Nanotechnology: A Powerful Combination against Breast Cancer.

Considerable advancements have been made in breast cancer therapeutics in the past few decades. However, the advent of chemo-resistance and adverse drug reactions coupled with tumor metastasis and recurrence posed a serious threat to combat this lethal disease. Novel anti-cancer agents, as well as new therapeutic strategies, are needed to complement conventional breast cancer therapies. The quest for developing novel anti-cancer drugs caused an upsurge in exploring and harnessing natural compounds, especially phytochemicals. Various research groups have explored and documented the anti-cancer potential of wide variety of phytochemical groups including flavonoids (curcumin, kaempferol, myricetin, quercetin, naringenin, apigenin, genistein epigallocatechin gallate), stilbenes (resveratrol), carotenoids (crocin, lycopene, lutein), and anthraquinone (Emodin). However, low chemical stability, poor water solubility, and short systemic half-life impede their clinical utility. The implication of nano-technological approaches to decode the pharmacokinetic challenges associated with phytochemical usage, as well as selective drug targeting, have markedly enhanced the pre-clinical anti-cancer activity, thus aiding in their clinical translation. This review documented the recent advances in utilizing phytochemicals for breast cancer prevention and lipidbased nanotechnological approaches for circumventing their pharmacokinetic concerns to enhance their systemic availability, cytotoxicity, and targeted delivery against breast cancer alone as well as in combination with conventional therapeutic agents.

On discovery of novel hub genes for ER+ and TN breast cancer types through RNA seq data analyses and classification models

Breast cancer (BC) is a malignant neoplasm which is classified into various types defined by underlying molecular factors such as estrogen receptor positive (ER+), progesterone receptor positive (PR+), human epidermal growth factor positive (HER2+) and triple negative (TNBC). Early detection of ER+ and TNBC is crucial in the choice of diagnosis and appropriate treatment strategy. Here we report the key genes associated to ER+ and TNBC using RNA-Seq analysis and machine learning models. Three ER+ and TNBC RNA seq datasets comprising 164 patients in-toto were selected for standard NGS hierarchical data processing and data analyses protocols. Enrichment pathway analysis and network analysis was done and finally top hub genes were identified. To come with a reliable classifier which could distinguish the distinct transcriptome patterns associated to ER+ and TNBC, ML models were built employing Naïve Bayes, SVM and kNN. 1730 common DEG’s exhibiting significant logFC values with 0.05 p-value threshold were identified. A list of top ten hub genes were screened on the basis of maximal clique centrality (MCC) which included CDC20, CDK1, BUB1, AURKA, CDCA8, RRM2, TTK, CENPF, CEP55 and NDC80.These genes were found to be involved in crucial cell cycle pathways. k-Nearest Neighbor (kNN) model was observed to be best classifier with accuracy 84%, specificity 66% and sensitivity 95% to differentiate between ER+ and TNBC RNA-Seq transcriptomes. Our screened list of 10 hub genes can thus help unearth novel molecular signatures implicated in ER+ and TNBC onset, prognosis and design of novel protocols for breast cancer diagnostics and therapeutics.

:Making Sense: Markets from Stories in New Breast Cancer Therapeutics

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Sophie Mützel. Making Sense: Markets from Stories in New Breast Cancer Therapeutics

Sophie Mützel. Making Sense: Markets from Stories in New Breast Cancer Therapeutics

Computational investigation of the anticancer potential of Sorghum bicolor and Setaria italica phytochemicals against dihydrofolate reductase (DHFR) enzyme

Breast and prostate cancer holds the position of foremost contributors to mortality. Dietary therapies for accompanied by medication are widely recognized as a potential method to successfully tackle cancer. Millet grains are the most ancient food, a perfect combination of proteins, carbohydrates, fiber, macronutrients, micronutrients, and vitamins. This study aims to examine the anticancer potential of Sorghum bicolor (Sorghum) and Setaria italica (Foxtail) phytochemicals. The 50 phytochemicals of sorghum and foxtail millets were retrieved through a literature survey and docked to the Dihydrofolate reductase (DHFR), an enzyme essential for cell growth and proliferation. The top-scoring phytochemicals were filtered and further investigated with active-site residue interaction, drug-likeness, and pharmacokinetics analysis. The ligand stability with the DHFR was evaluated through density functional theory (DFT) based HOMO and LUMO calculations. The results show that caffeic acid, ferulic acid, hesperetic acid, stigmasterol, Cis-p-Coumaric acid, and luteolinidin attained greater stability within the active site of DHFR. These phytochemicals showed a docking score of − 6.4 kcal/mol, − 6.4 kcal/mol, − 6.1 kcal/mol, − 6.4 kcal/mol, − 5.4 kcal/mol, and − 6.7 kcal/mol with DHFR (PDB ID:1BOZ) and flutamide and capecitabine have docking score of − 7.5 and − 8.1 for 1BOZ and − 7.4 and − 7.1 with DHFR (PDB ID:1OHK) respectively. The dynamic interaction at the molecular level validated the stability of these phytochemicals against both DHFR target proteins along with excellent drug-likeness and pharmacokinetic properties. However, the current findings were proven and validated through in-silico experiments to validate above identified phytochemicals as DHFR inhibitors, so millets are used as therapeutics for breast and prostate cancer.

Facile Synthesis of Hemin Derivatives with Modulated Aggregation Behaviour and Enhanced Nitric‐Oxide Scavenging Properties as New Therapeutics for Breast Cancer

Nitric oxide (•NO) plays various pathophysiological roles in breast cancer, significantly influencing the migration of tumour cells through concentration gradients. Therefore, modulating •NO levels via selective scavenging presents a promising approach to treating aggressive •NO‐dependent cancers, such as triple‐negative breast cancer (TNBC). Hemin emerges as a potential scavenger of •NO; however, its metalloporphyrin molecules tend to aggregate in physiological solutions, which limits its biomedical applications. To address this, a modification strategy is employed to minimize aggregation and protect against physiological oxidative degradation while preserving •NO‐scavenging properties. This is achieved through a simple chemical transformation that involves hemin conjugation to aromatic residues, tyrosine, and tyramine via carbodiimide reactions. These derivatives exhibit altered electronic properties and oxidation potential compared to hemin, alongside reduced aggregation tendencies and retained •NO‐binding affinity in aqueous solutions. Furthermore, depending on the type of hemin derivative, there is an associated inhibition of TNBC cell migration. These model hemin compounds demonstrate varying •NO‐binding affinities and resistance levels to oxidative degradation and aggregation, offering insights into the design of •NO‐scavenging molecules with enhanced properties for cancer treatment.

Chemical characterization and cytotoxic effect of three edible fungi (Morchella) against breast cancer cells: A therapeutic approach

Current breast cancer therapeutics are associated with short-term efficacy, increased drug resistance, and severe adverse reactions, thus demanding the development of new therapeutic approaches. This present study aimed to explore the cytotoxic activity of Morchella extracts in the context of the MCF-7 cell line (breast cancer) and ultra-performance liquid chromatography mass spectroscopy (UPLC-MS) analysis. The cytotoxic activity of the Morchella conica, Morchella delicosa, and Morchella escuelnta extracts was examined against the breast cancer cell line (MCF-7), using a 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay (MTT assay). The Morchella extracts were screened for the presence of compounds using ultra-performance liquid chromatography mass spectroscopy (UPLC-MS/MS) based analysis. All the Morchella extracts actively restricted the viability and proliferation of breast cancer cells in a dose-dependent manner, with half maximal inhibitory concentration (IC50) values ranging from 0.017 to 0.68 mg/ml. The main compounds identified in Morchella include alkaloid, sterol, flavonoid, terpenoid, fatty acid, peptide, glutamic acid, amino acid, coumarin, and cyclopyrrolone. In conclusion, Morchella extracts exhibited cytotoxic effects against breast cancer cell lines and decreased the viability of MCF-7 cell line. The Morchella compounds might be the main components contributing to the inhibition of breast cancer cells. The findings of this research offer an innovative framework for advanced investigations for the development of cancer therapeutics from this fungus.

SPACA6P-AS: a trailblazer in breast cancer pathobiology and therapeutics

ObjectiveThe primary objective of this investigation is to delve into the involvement of the long noncoding RNA (lncRNA) SPACA6P-AS in breast cancer (BC) development, focusing on its expression pattern, association with clinical-pathological features, impact on prognosis, as well as its molecular and immunological implications.MethodsBioinformatics analysis was conducted utilizing RNA sequencing data of 1083 BC patients from the TCGA database. Functional exploration of SPACA6P-AS was carried out through the construction of survival curves, GO and KEGG enrichment analysis, and single-sample gene set enrichment analysis (ssGSEA). Furthermore, its functionality was validated through in vitro cell experiments and in vivo nude mouse model experiments.ResultsSPACA6P-AS showed a remarkable increase in expression levels in BC tissues (p < 0.001) and demonstrated a close relationship to poor prognosis (overall survival HR = 1.616, progression-free interval HR = 1.40, disease-specific survival HR = 1.54). Enrichment analysis revealed that SPACA6P-AS could impact biological functions such as protease regulation, endopeptidase inhibitor activity, taste receptor activity, taste transduction, and maturity-onset diabetes of the young pathway. ssGSEA analysis indicated a negative correlation between SPACA6P-AS expression and immune cell infiltration like dendritic cells and neutrophils, while a positive correlation was observed with central memory T cells and T helper 2 cells. Results from in vitro and in vivo experiments illustrated that silencing SPACA6P-AS significantly inhibited the proliferation, migration, and invasion capabilities of BC cells. In vitro experiments also highlighted that dendritic cells with silenced SPACA6P-AS exhibited enhanced capabilities in promoting the proliferation of autologous CD3 + T cells and cytokine secretion. These discoveries elucidate the potential multifaceted roles of SPACA6P-AS in BC, including its potential involvement in modulating immune cell infiltration in the tumor microenvironment.ConclusionThe high expression of lncRNA SPACA6P-AS in BC is closely linked to poor prognosis and may facilitate tumor progression by influencing specific biological processes, signaling pathways, and the immune microenvironment. The regulatory role of SPACA6P-AS positions it as a prospective biomarker and target for therapeutic approaches for BC diagnosis and intervention.

Graphene Oxide Nanocarriers for Effective Drug Delivery in Breast Cancer Treatment

Breast cancer is the most commonly diagnosed form of cancer globally, with women having a higher risk of developing the disease. Current treatment approaches, such as surgery, chemotherapy, and radiotherapy, encounter significant difficulties due to the heterogeneous and intricate regulation of tumors. Nanotechnology, especially the utilization of graphene oxide (GO), presents a promising approach to overcoming the limitations of traditional treatments. GO&amp;apos;s unique properties, including its two-dimensional structure, functional groups, and high surface area, make it an ideal material for developing multifunctional nanocarriers. Graphene oxide-based nanocarriers have demonstrated immense potential in breast cancer therapeutics by overcoming the limitations and adverse reactions associated with chemotherapy. The functionalization of GO&amp;apos;s surface using biocompatible substances like chitosan and polyethylene glycol improves the cytotoxicity of GO. Enhancing the cytotoxicity also improves the ability to treat tumors that have developed resistance to traditional treatments. These findings demonstrate the promising efficacy of GO-based nanocarriers in treating breast cancer and pave the way for the development of more precise and efficient treatment strategies in the future, potentially improving therapeutic outcomes.

Timeliness of breast cancer care: Real-world experience at a tertiary care and a public safety-net hospital.

e13712 Background: Advances in breast cancer diagnostics and therapeutics have led to early cancer detection and an overall decrease in morbidity and mortality rates; nevertheless, cancer care disparity still exists and highlights areas of unmet need in cancer care delivery. Cancer navigator programs have been used as a strategy to reduce disparities arising from social determinants of health. We compared the timeliness of breast cancer care at UCLA Medical Center (UCLA), a tertiary care academic hospital, and at Olive View-UCLA Medical Center (OVMC), a safety-net hospital. This study highlights the benefits of cancer care navigation and streamlined workflow processes in bridging disparity gaps. Methods: In this retrospective cohort study, we examined patients diagnosed with breast cancer between 2018 and 2019 at UCLA and OVMC. A total of 100 patients were identified at each site. Demographics data, including age, race, ethnicity, pathology, and staging, were collected. For time interval analysis along the breast cancer care timeline, the mean number of days from the initial imaging date (i.e. either screening or diagnostic mammogram, with the latter if the patient presented with signs and symptoms of breast cancer) was compared with each diagnostic and therapeutic time point. These included time between screening and diagnostic mammograms (if available), time to biopsy, time to MRI, time to surgery, and time to treatment. Results: Mean age (years) at diagnosis was 62.0 and 57.5 at UCLA and OVMC, respectively (p=0.024). Racial distribution showed 60% White, 14% Asian, 7% Black, 7% Mixed, and 4% Other at UCLA, compared to 72%, 9%, 5%, 0%, and 0% at OVMC, respectively (p=0.01). Ethnicity comparison showed 11% Hispanic/Latino at UCLA versus 52% at OVMC (p&lt;0.001). Breast cancer stage at diagnosis was not significantly different between sites. The time interval (days) from screening to diagnostic mammogram was significantly longer at OVMC compared to UCLA (35.1 versus 14.6, p=0.007); however, no statistically significant differences were observed from time to biopsy (27.3 versus 29.5, p=0.651), time to MRI (54.7 versus 49.9, p=0.703), time to neoadjuvant chemotherapy (73.4 versus 48.7, p=0.236), time to surgery (97.2 versus 106.2, p=0.523), time to adjuvant chemotherapy (158.6 versus 139.5, p=0.4), and time to radiation therapy (192.9 versus 198.6, p=0.796) between UCLA and OVMC, respectively. Conclusions: Our study shows that the timeliness of breast cancer care at UCLA and OVMC was overall comparable. This result can be attributed to the implementation of cancer navigator programs at OVMC as well as streamlined breast cancer detection workflow developed in multi-disciplinary collaboration across numerous departments. We believe this workflow can be expanded to all tumor types and be shared with other safety net facilities in order to bridge gaps in cancer care delivery for oncology patients.

Identification of small molecular inhibitors of SIRT3 by computational and biochemical approaches a potential target of breast cancer

Sirtuin 3 (SIRT3) belongs to the Sirtuin protein family, which consists of NAD+-dependent lysine deacylase, involved in the regulation of various cellular activities. Dysregulation of SIRT3 activity has been linked to several types of cancer, including breast cancer. Because of its ability to stimulate adaptive metabolic pathways, it can aid in the survival and proliferation of breast cancer cells. Finding new chemical compounds targeted towards SIRT3 was the primary goal of the current investigation. Virtual screening of ~ 800 compounds using molecular docking techniques yielded 8 active hits with favorable binding affinities and poses. Docking studies verified that the final eight compounds formed stable contacts with the catalytic domain of SIRT3. Those compounds have good pharmacokinetic/dynamic properties and gastrointestinal absorption. Based on excellent pharmacokinetic and pharmacodynamic properties, two compounds (MI-44 and MI-217) were subjected to MD simulation. Upon drug interaction, molecular dynamics simulations demonstrate mild alterations in the structure of proteins and stability. Binding free energy calculations revealed that compounds MI-44 (− 45.61 ± 0.064 kcal/mol) and MI-217 (− 41.65 ± 0.089 kcal/mol) showed the maximum energy, suggesting an intense preference for the SIRT3 catalytic site for attachment. The in-vitro MTT assay on breast cancer cell line (MDA-MB-231) and an apoptotic assay for these potential compounds (MI-44/MI-217) was also performed, with flow cytometry to determine the compound’s ability to cause apoptosis in breast cancer cells. The percentage of apoptotic cells (including early and late apoptotic cells) increased from 1.94% in control to 79.37% for MI-44 and 85.37% for MI-217 at 15 μM. Apoptotic cell death was effectively induced by these two compounds in a flow cytometry assay indicating them as a good inhibitor of human SIRT3. Based on our findings, MI-44 and MI-217 merit additional investigation as possible breast cancer therapeutics.

TRPV1-Dependent Antiproliferative Activity of Dioecious Maclura pomifera Extracts in Estrogen Receptor-Positive Breast Cancer Cell Lines Involves Multiple Apoptotic Pathways.

Globally, breast cancer is a significant cause of mortality. Recent research focused on identifying compounds regulating the transient receptor potential vanilloid 1 (TRPV1) ion channel activity for the possibility of developing cancer therapeutics. In this study, the antiproliferative properties and mechanisms of action through TRPV1 of Maclura pomifera, a dioecious tree native to the south-central USA, have been investigated. Male and female extracts of spring branch tissues and leaves (500 µg/mL) significantly reduced the viability of MCF-7 and T47D cells by 75-80%. M. pomifera extracts induced apoptosis by triggering intracellular calcium overload via TRPV1. Blocking TRPV1 with the capsazepine antagonist and pretreating cells with the BAPTA-AM chelator boosted cell viability, revealing that M. pomifera phytochemicals activate TRPV1. Both male and female M. pomifera extracts initiated apoptosis through multiple pathways, the mitochondrial, ERK-induced, and endoplasmic reticulum-stress-mediated apoptotic pathways, demonstrated by the expression of activated caspase 3, caspase 9, caspase 8, FADD, FAS, ATF4, and CHOP, the overexpression of phosphorylated PERK and ERK proteins, and the reduction of BCL-2 levels. In addition, AKT and pAKT protein expressions were reduced in female M. pomifera-treated cells, revealing that female plant extract also inhibits PI3K/Akt signaling pathways. These results suggest that phytochemicals in M. pomifera extracts could be promising for developing breast cancer therapeutics.

Abstract ED08-02: Next generation therapeutics in hormone positive breast cancer: balancing efficacy and tolerability

Abstract The past several years have brought a wealth of new and emerging novel agents for the management of both early and advanced hormone repcetor positive breast cancer, including inhibitors of PIK3CA, mTOR, AKT, CDK4/6, PARP, as well as oral SERDs. These agents have significantly improved survival outcomes for many patients, but progress may come at the cost of specific and sometimes challeging side effects, whcih may threaten the ability to keep a patient on a therapy that is providing benefit. We will review a spectrum of agents, the expected side effect profiles, and strategies to mitigate toxicity and maximize therapeutic index. Citation Format: E. Mayer. Next generation therapeutics in hormone positive breast cancer: balancing efficacy and tolerability [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr ED08-02.

Abstract PO1-24-06: Prolactin Hormone-Induced Mammary Differentiation and Anti-tumorigenic Role in Breast Cancer

Abstract The premise of differentiation therapy in cancer is a strategy that aims at engaging-forward differentiation and cellular reprograming restricting the proliferative, tumor repopulation, stemness, EMT and metastatic capacities of tumor cells leading to the cessation of the aggressive tumor phenotype and offering the cancer patients improved survival for decades. Therefore, deciphering molecular mechanisms deriving differentiation in normal mammary and breast cancer cells may allow the discovery of innovative differentiation-based biomarkers and therapeutics in breast cancer. Lactation is an intricate process that results in the ability of the breast cells to produce a complex nutritious biological fluid to nurse the new-born. While the beneficial effects of breastfeeding to the infant is irrefutable, its effects on maternal health are less investigated especially in relation to breast cancer that still affects 1 in 8 women in high income countries and 1 in 20 globally. Importantly, epidemiological studies have linked breastfeeding to reduced risk of breast cancer by promoting terminal differentiation of the breast epithelial cells. While breastfeeding process is regulated by multiple hormones, growth factors, and transcriptional regulators, the lactation hormone prolactin (PRL) is known to be directly implicated in the hormonal control of breastfeeding. Extensive research including our own work has shown that PRL/PRL receptor (PRLR) pathway derives mammary gland development and importantly mammary epithelial cell terminal differentiation allowing successful lactation. In contrast the role of PRL in breast cancer is still to be fully defined. Importantly, we have accumulated compelling evidence using in-silico publicly available patient data sets and molecular data implicating this pathway as a clinically relevant pro-differentiation pathway driving differentiation and cellular reprograming suppressing stemness, EMT, metastasis and tumorigenesis in breast cancer. To better characterize PRL signaling mediating its pro-differentiation effects, we used large-scale unbiased proteomics analysis of PRLR/interacting proteins in breast cancer cells. Our analyses revealed several novel PRLR-interactors. We have further confirmed these interactions through co-immunoprecipitations/western blotting analyses in breast cancer cells representative the different breast cancer subtypes. We also examined their functional contributions to mammary differentiation and tumorigenesis using in vitro and in vivo assays. Moreover, we defined their potential clinical relevance using bioinformatics in silico databases of breast cancer. Together our study delineates novel PRL/PRLR-downstream signaling mediators important for mammary differentiation and tumorigenesis and may thus be useful as biomarkers and/or therapeutic targets in breast cancer. Citation Format: Dana Hamam, Suhad Ali. Prolactin Hormone-Induced Mammary Differentiation and Anti-tumorigenic Role in Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-24-06.

Abstract PO3-29-04: Patient selection for high RSK2 expression is key for achieving improved PFS in metastatic breast cancer in the PMD-026 Phase 1/1b study

Abstract Background: PMD-026 is a first in class, reversible, oral small molecule inhibitor of p90 ribosomal S6 kinase (RSK), a kinase family activated by the MAPK and PDK-1 pathways, which regulate substrates involved in cancer cell proliferation and drug resistance. Both pathways are implicated in HR+ and triple negative breast cancer (TNBC). RSK2 can modulate the growth of breast cancer (BC) by promoting cell cycle progression through G2/M, specifically through pYB-1S102 which nucleates spindle pole formation in M-phase of cancer cells. This mechanism of action (MOA) for PMD-026 can be monitored by measuring the loss of pYB-1S102 and pCDK2Y15, a marker for G2/M arrest. Therefore, PMD-026 presents a novel mechanism to inhibit resistance at G1/S which is common for CDK4/6 inhibitors as well as ADCs such as those that contain Topoisomerase 1 conjugates. Here in, we show for the first time that PMD-026 inhibits P-YB-1S102 and pCDK2y15 in a dose-dependent manner in TNBC cells and address whether this could be translated as a pharmacodynamic marker of PMD-026 activity in patients. To guide patient selection, we are co-developing a unique and simple IHC based companion diagnostic (CDx) with Roche based on the principle that activated RSK2 translocates from the cytoplasm into the nucleus. In mBC, RSK2 was found to be highly expressed in ~70% of patients using a staining algorithm. An H-score was developed and ultimately H-score &amp;gt;180 (75% nuclear staining with staining intensity of 2+ or 3+ by IHC) was used as the cut-off in our Phase 1/1b trial retrospective study. This IHC assay will be used to select patients in the upcoming Phase II, as PFS in the PMD-026 Phase I/1b study showed remarkable differences when comparing patients with high and low RSK2. Results: In this Phase 1/1b study, PMD-026 was evaluated in an ethnically diverse population of women across all breast cancer subtypes. Patients had a median of 5 prior lines of therapy and PMD-026 achieved stable disease in 44% (11/25) of the subjects. Consistent with the MOA, PMD-026 inhibited pCDK2Y15 in PBMCs from patients at C1D15. Corresponding plasma concentrations were ~ 1µM, which correlates with the IC90 of PMD-026 in preclinical models. To guide patient selection in the future, the RSK2 IHC with an H:Score &amp;gt;180 was used to evaluate patient outcomes. Using this criterion, PFS was significantly longer in RSK2 high vs low patients (3.6 months vs 1.3 month, HR = 0.27, p = 0.031, N=20 patients representing de novo TNBC and HR+/CDK4/6 refractory subtypes). Upon further analysis, patients who had 5 lines of therapy or less benefited the most. PFS in these less heavily pretreated RSK2 high patients was 4.8 months vs 1.3 months for RSK2 low patients (HR = 0.07, p = 0.001 N=14 representing the same subtypes above). It was clear that the time on study was longer for patients with high RSK2 vs low, and this was specifically noted in de novo TNBC and HR+ patients that previously failed CDK4/6 inhibitors as well as endocrine therapies. A key observation in this study was that the PFS benefit was based on the RSK2 levels and not on any pharmacokinetic differences between patients, as the AUC (p=0.53), Cmax (p=0.73) and plasma levels (p=0.76) did not differ between RSK2 high and RSK2 low groups. These data strongly support the activity of this first in class RSK inhibitor, PMD-026, in RSK2 high breast cancers. Our integrated IHC based CDx strategy plans to prospectively enroll RSK2 high patients for our Phase 2 trials will be described. Conclusions/Translational Significance: CDx guided breast cancer therapeutics are often lacking for the treatment of TNBC, as well as HR+ breast cancers that have failed CDK4/6 inhibitors. The ability to identify patients who could potentially benefit most from RSK-targeted agents such as PMD-026 is an important step forward in delivering practice changing therapies for patients. Citation Format: Sandra Dunn, Judy Wang, Hyo Han, Robert Wesolowski, Amita Patnaik, Shakeela Bahadur, Nicolaos Palaskas, My-my Huynh, Aarthi Jayanthan, Gerrit Los, Andrew Dorr. Patient selection for high RSK2 expression is key for achieving improved PFS in metastatic breast cancer in the PMD-026 Phase 1/1b study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-29-04.