Aggressive Type Of Breast Cancer Research Articles

Abstract C037: Inflammatory breast cancer by metastatic status: Racial and ethnic and socioeconomic disparities in receipt of treatment

Abstract Background: Inflammatory breast cancer (IBC) is a relatively rare but aggressive type of breast cancer. Racial and ethnic minority patients are disproportionately affected by IBC and often face barriers to accessing cancer care and services. However, racial and ethnic disparities in receipt of treatment are not well defined among patients with IBC by metastatic status. Methods: We analyzed data from patients with IBC in the 2004-2020 U.S. National Cancer Database. Five treatment modalities were assessed: hormone therapy, chemotherapy, radiotherapy, surgery, and trimodal therapy. Metastatic status was dichotomous as “metastatic/non-metastatic.” Racial and ethnic groups included Asian or Pacific Islander, American Indian, Alaska Native, or Other, Black, Hispanic, and White. Separate logistic regression models were fit, adjusting for sociodemographic and clinicopathological characteristics, stratified by metastatic status. Adjusted odds ratios (aOR) and 95% CIs were calculated. Results: Of 33,376 patients with IBC (mean age 58 years [SD=14]), most (70.6%) identified as White, followed by 18.1% as Black, 7.0% as Hispanic, 2.5% as Asian or Pacific Islander, 1.8% as American Indian, Alaska Native, or Other; and 32.5% were metastatic. In the non-metastatic cohort, Black (72.7%; aOR 0.79, 95% CI: 0.63-0.98) or Asian or Pacific Islander (74.8%; aOR 0.59, 95% CI: 0.38-0.90) patients had lower odds of receiving hormone therapy than White patients (78.0%). Compared with White patients, Black patients had a lower likelihood of receiving chemotherapy (89.1% vs. 89.5%; aOR 0.67, 95% CI: 0.53-0.86), surgery (78.4% vs. 85.3%; aOR 0.65, 95% CI: 0.55-0.77), or trimodal therapy (81.5% vs. 87.3%; aOR 0.61, 95% CI: 0.49-0.76). American Indian, Alaska Native, or Other (65.0%; aOR 0.64, 95% CI: 0.42-0.97) and Black (63.6%; aOR 0.71, 95% CI: 0.61-0.82) patients had lower odds of receipt of radiotherapy than White patients (70.6%). In the metastatic cohort, Black patients had a lower likelihood of receiving hormone therapy (55.2% vs. 63.5%; aOR 0.61, 95% CI: 0.48-0.78), chemotherapy (78.7% vs. 78.2%; aOR 0.75, 95% CI: 0.60-0.95), surgery (28.2% vs. 35.1%; aOR 0.68, 95% CI: 0.56-0.82), or trimodal therapy (30.4% vs. 40.4%; aOR 0.63, 95% CI: 0.48-0.82) than White patients. There were no statistically significant differences in receipt of treatment between White and other racial and ethnic patients with metastatic IBC. Furthermore, we observed significantly differential rates of treatment receipts by socioeconomic factors including median household income quartile, insurance coverage, and facility type. Conclusions: In this study of a large U.S. national IBC patient cohort, racial and ethnic minority patients were less likely than White patients to have received treatment for IBC, with Black patients being the most affected. Our findings highlight racial and ethnic disparities and socioeconomic inequities in treatment receipts, suggesting the need for oncology programs to improve equitable care access and reduce these disparities in the IBC population. Citation Format: Jincong Q. Freeman, Jared H. Hara, Olasubomi J. Omoleye. Inflammatory breast cancer by metastatic status: Racial and ethnic and socioeconomic disparities in receipt of treatment [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C037.

Abstract C141: Inactivating the mitotic kinases TTK and NEK2 as a promising approach for the reduction of metastasis in triple-negative breast cancer in non-Hispanic Blacks and Hispanic/Latinas

Abstract Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer in women worldwide. It is associated with uncontrolled cell proliferation, increased rates of centrosome amplification, genetic instability, and invasive capacity. Advanced stages of TNBC with distant metastasis are virtually incurable, with chemotherapy as the primary treatment option. Non- Hispanic Black (NHB) and Hispanic/Latino (H/L) women have lower 5-year survival rates when compared to non-Hispanic White (NHW) women with breast cancer, in part because their breast tumors are detected at higher stages, and due to elevated rates of TNBC. Women with a higher percentage of African ancestry have been shown to have a higher expression of multiple mitotic kinases. Mitotic kinases, such as TTK, maintain genomic integrity, while NEK2 modulates centrosome separation and microtubule organization. However, their overexpression in breast cancer is associated with cell proliferation, chromosome instability, aneuploidy, and early stages of metastasis (the epithelial-to-mesenchymal transition, or EMT, cell migration and invasion). A tissue microarray confirmed associations between TTK overexpression, proliferation, and EMT markers in breast tumors and the TNBC subtype. Thus, we aim to measure protein and mRNA expression levels of EMT markers upon downregulation of TTK and NEK2. To address this, mesenchymal TNBC cell lines, MDA-MB-231 (NHW) or MDA-MB-157 (NHB), were cultured in DMEM and 10% FBS, followed by TTK siRNA, NEK2 siRNA, or double transfection. TRIzol was then used for protein and RNA extraction. Western blot and qPCR analyses measured EMT markers' protein and mRNA expression levels, respectively. Preliminary results from these experiments showed that silencing of TTK, NEK2, or TTK/NEK2 resulted in a reduction of the mRNA expression levels of Vimentin, N-cadherin, and β-Catenin in MDA-MB- 231 cell lines. Moreover, data showed a decrease in Vimentin in all treatment groups at the protein level. TTK/NEK2 knockdown also reduced N-cadherin and β-Catenin protein expression levels. These preliminary data suggest that silencing of mitotic kinases TTK and NEK2 may be a promising approach for targeting early stages of metastasis in TNBCs. Because of their increased expression in women of African heritage, anti-mitotic kinase inactivation can be a novel approach that can highly benefit women of the West African diaspora with breast cancer, including African American and Caribbean Hispanics, specifically by diminishing cancer cell survival and metastasis. Citation Format: Alexandra N Aquino-Acevedo, Ángel D. Colón-Burgos, Gretchen M. Albarrán-Acosta, Marileana Rodríguez-Ruiz, Joel A. Orengo-Orengo, Melanie E. Cruz- Robles, Harold I. Saavedra. Inactivating the mitotic kinases TTK and NEK2 as a promising approach for the reduction of metastasis in triple-negative breast cancer in non-Hispanic Blacks and Hispanic/Latinas [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C141.

A novel combinatorial approach usingsulforaphane- and withaferin A-rich extracts for prevention of estrogen receptor-negative breast cancer through epigenetic and gut microbial mechanisms.

Estrogen receptor-negative [ER(-)] mammary cancer is the most aggressive type of breast cancer (BC) with higher rate of metastasis and recurrence. In recent years, dietary prevention of BC with epigenetically active phytochemicals has received increased attention due to its feasibility, effectiveness, and ease of implementation. In this regard, combinatorial phytochemical intervention enables more efficacious BC inhibition by simultaneously targeting multiple tumorigenic pathways. We, therefore, focused on investigation of the effect of sulforaphane (SFN)-rich broccoli sprouts (BSp) and withaferin A (WA)-rich Ashwagandha (Ash) combination on BC prevention in estrogen receptor-negative [ER(-)] mammary cancer using transgenic mice. Our results indicated that combinatorial BSp + Ash treatment significantly reduced tumor incidence and tumor growth (~ 75%) as well as delayed (~ 21%) tumor latency when compared to the control treatment and combinatorial BSp + Ash treatment was statistically more effective in suppressing BC compared to single BSp or Ash intervention. At the molecular level, the BSp and Ash combination upregulated tumor suppressors (p53, p57) along with apoptosis associated proteins (BAX, PUMA) and BAX:BCL-2 ratio. Furthermore, our result indicated an expressional decline of epigenetic machinery HDAC1 and DNMT3A in mammary tumor tissue because of combinatorial treatment. Interestingly, we have reported multiple synergistic interactions between BSp and Ash that have impacted both tumor phenotype and molecular expression due to combinatorial BSp and Ash treatment. Our RNA-seq analysis results also demonstrated a transcriptome-wide expressional reshuffling of genes associated with multiple cell-signaling pathways, transcription factor activity and epigenetic regulations due to combined BSp and Ash administration. In addition, we discovered an alteration of gut microbial composition change because of combinatorial treatment. Overall, combinatorial BSp and Ash supplementation can prevent ER(-) BC through enhanced tumor suppression, apoptosis induction and transcriptome-wide reshuffling of gene expression possibly influencing multiple cell signaling pathways, epigenetic regulation and reshaping gut microbiota.

Racial and survival disparities in inflammatory breast cancer (IBC) and non-IBC: a population-based study focused on Native Hawaiians and other Pacific Islanders.

It is well known that race is an independent predictor of breast cancer mortality and advanced stage at diagnosis. Inflammatory breast cancer (IBC) is the most aggressive type of breast cancer and has distinct clinical and biological features. Previous studies have shown that Blacks have a higher incidence of IBC than Whites. However, the proportion of IBC and the role of race on prognosis in Native Hawaiian and other Pacific Islander (NH/PI) populations with breast cancer are poorly understood. In this study, we aimed to examine the proportion of IBC to non-IBC in NH/PIs and to identify the clinicopathological, biological, and socioeconomic factors associated with the overall survival of NH/PIs compared to other races. Utilizing a comprehensive cancer registry from the largest hospital in Hawaii, newly diagnosed primary invasive breast cancer patients diagnosed between 2000 and 2018 were identified. Univariate and multivariate Cox proportional hazards models were used to test the association between race and clinical outcomes. Variables with P-values <0.05 in the univariate analysis and race (variable of interest) were included in a multivariate analysis. The cohort included 3691 patients, 60 of whom had IBC. NH/PI race had the highest proportion of IBC compared to other races (3.44%) but was not found to be an independent poor prognostic factor in IBC (HR 1.17 [95%CI 0.26-5.22]). Conversely, NH/PI race was associated with worse survival outcomes in patients with non-IBC (HR 1.65 [95%CI, 1.14-2.39]) along with other factors such as lack of insurance, underinsured status, triple-negative breast cancer (TNBC) subtype, age, and advanced clinical stage. The findings of this study highlight that NH/PIs had higher rates of IBC and inferior survival in non-IBC compared to other races but not in IBC. It is essential to disaggregate NH/PI race from Asians in future population-based research studies. Further research is needed to understand the factors contributing to higher rates of IBC and poor survival outcomes in NH/PIs with non-IBC as well as targeted interventions to improve breast cancer outcomes in this population to ultimately help improve survival rates and reduce health inequities in NH/PIs with breast cancer.

Research hotspots and frontiers of neoadjuvant therapy in triple-negative breast cancer: a bibliometric analysis of publications between 2002 and 2023.

Triple-negative breast cancer (TNBC) is a highly aggressive type of breast cancer with poor prognosis, and neoadjuvant therapy (NAT) has emerged as an important component in managing advanced-stage patients by providing surgical opportunities and improving survival outcomes. A search of publications on NAT for TNBC from 2002 to 2023 was conducted through the Web of Science core collection. A comprehensive bibliometric analysis was conducted on the data using CiteSpace, VOSviewer, and Bibliometrix. The analysis revealed a continuous and steady growth in the number of articles published in this field over the past 20 years. The United States has made significant contributions to this field, with The University of Texas MD Anderson Cancer Center publishing the most articles. Loibl, S. from Germany was found to be the most published author with 54 articles. Analysis of the journals showed that the Journal of Clinical Oncology is the most cited journal. Combined with the keyword co-occurrence analysis and clustering analysis, current research topic focuses on treatment regimens and disease prognosis. Dual-map overlay of the journals indicates that the research trend is gradually shifting from molecular biology and genetics to immunology and clinical research. Combination therapy, including immunotherapy, may be the future direction for NAT treatment of TNBC. Overall, this study provides valuable insights into the current research status, latest advancements, and emerging development trend of NAT for TNBC.

Towards a More Efficient Breast Cancer Therapy Using Active Human Cell Membrane-Coated Metal–Organic Frameworks

The recent description of well-defined molecular subtypes of breast cancer has led to the clinical development of a number of successful molecular targets. Particularly, triple-negative breast cancer (TNBC) is an aggressive type of breast cancer with historically poor outcomes, mainly due to the lack of effective targeted therapies. Recent progresses in materials science have demonstrated the impressive properties of metal–organic framework nanoparticles (NPs) as antitumoral drug delivery systems. Here, in a way to achieve efficient bio-interfaces with cancer cells and improve their internalization, benchmarked MIL-100(Fe) NPs were coated with cell membranes (CMs) derived from the human TNBC cell line MDA-MB-468. The prepared CMs-coated metal–organic framework (CMs_MIL-100(Fe)) showed enhanced colloidal stability, cellular uptake, and cytotoxicity in MDA-MB-468 cells compared to non-coated NPs, paving the way for these human CMs-coated MIL-100(Fe) NPs as effective targeted therapies against the challenging TNBC.

Chlorin Conjugates in Photodynamic Chemotherapy for Triple-Negative Breast Cancer.

Breast cancer (BC) is the most common type of cancer in women and the number of new cases in the US is still increasing each year. Triple-negative breast cancer (TNBC), which comprises 15-20% of all breast cancer, is a heterogeneous disease and is considered the most aggressive type of breast cancer due to the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expressions for treatments. Traditional chemotherapy is the standard protocol for the treatment of TNBC. Toxicity and multidrug resistance are major drawbacks to chemotherapy. The lack of molecular targets and poor prognosis for TNBC prompts an urgent need to discover novel therapeutic strategies to improve clinical outcomes and quality of life for patients. Photodynamic therapy (PDT) or light treatment is a binary anti-cancer procedure that uses a photosensitizer (PS) that, upon light activation, produces cytotoxic oxygen species, destroying tumor cells. PDT is minimally invasive and can be repeated a few times without accumulating significant toxicity in the surrounding tissues. The primary goal of this study was to investigate in vitro photodynamic chemotherapy as a ternary combination therapy using our synthesized photosensitizers (chlorin-vitamin conjugates and their corresponding indium complexes) co-treated with known chemotherapeutic agents (taxol, doxorubicin, cisplatin, fluorouracil, or methotrexate) in the presence of light and determine the optimum conditions as a pre-clinical study of an enhanced tumoricidal effect against TNBC. Our results indicated that the best combination for an effective chemophotodynamic effect involves a ternary treatment of the indium complex of the chlorin-lipoic acid conjugate (InCLA) co-treated with taxol, which exhibited strong synergism at the nanomolar concentration when combined in the presence of visible light irradiation. Other ternary combinations containing taxol with a synergistic anti-tumor effect against TNBC include chlorin-pantothenic acid (CPA) and chlorin-biotin (CBTN) conjugates. Several other ternary combinations containing InCLA, CBTN, and CPA with either cisplatin, fluorouracil, or methotrexate were identified to generate a synergistic or additive effect. The light dosage remained constant, but the dosages of photosensitizers and chemotherapy drugs were varied to obtain the lowest possible concentration for the desired effect. The synergistic, additive or antagonistic effects of the drug combinations were determined based on the Chou-Talalay method, with InCLA-taxol having the lowest combination index (CI) of 0.25. Fluorescence and transmission electron microscopy (TEM) images provided evidence of apoptosis as the preferred mode of cell death. Our study demonstrated the combination of PDT and chemotherapy as a potential treatment option for TNBC patients.

Mitochondria-targeted ruthenium complexes can be generated in vitro and in living cells to target triple-negative breast cancer cells by autophagy inhibition

Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer, which owned severe resistance to platinum-based anticancer agents. Herein, we report a new metal-arene complex, Ru-TPE-PPh3, which can be synthesized in vitro and in living cells with copper catalyzed the cycloaddition reaction of Ru-azide and alkynyl (CuAAC). The complex Ru-TPE-PPh3 exhibited superior inhibition of the proliferation of TNBC MDA-MB-231 cells with an IC50 value of 4.0 μM. Ru-TPE-PPh3 could induce the over production of reactive oxygen species (ROS) to initiate the oxidative stress, and further damage the mitochondria both functionally and morphologically, as loss of mitochondrial membrane potential (MMP) and cutting the supply of adenosine triphosphate (ATP), the disappearance of cristae structure. Moreover, the damaged mitochondria evoked the occurrence of mitophagy with the autophagic flux blockage and cell death. The complex Ru-TPE-PPh3 also demonstrated excellent anti-proliferative activity in 3D MDA-MB-231 multicellular tumor spheroids (MCTSs), indicating the potential to inhibit solid tumors in living cells. This study not only provided a potent agent for the TNBC treatment, but also demonstrated the universality of the bioorthogonally catalyzed lethality (BCL) strategy through CuAAC reation.

Clinical Advances in Triple Negative Breast Cancer Treatment: Focus on Poly (L-lactide-coglycolide) Nanoparticles.

Triple negative breast cancer (TNBC) is the most aggressive type of breast cancer and is associated with high probability of metastasis and poor prognosis. Chemotherapeutics and surgery remain the most common options for TNBC patients; however, chemotherapeutic resistance and relapse of tumors limit the progression free survival and patient life span. This review provides an overview of recent chemotherapeutics that are in clinical trial, and the combination of drugs that are being investigated to overcome the drug resistance and to improve patient survival in different molecular subtypes of TNBCs. Nanotherapeutics have emerged as a promising platform for TNBC treatment and aim to improve the selectivity and solubility of drugs, reduce systemic side effects, and overcome multi-drug resistance. The study explores the role of nanoparticles for TNBC treatment and summarizes the types of nanoparticles that are in clinical trials. Poly(L-lactide-co-glycolide) (PLGA) is the most studied polymeric carrier for drug delivery and for TNBC treatment in research and in clinics. This review is about providing recent advancements in PLGA nanotherapeutic formulations and their application to help treat TNBC. Some background on current chemotherapies and pathway inhibitors is provided so that the readers are aware of what is currently considered for TNBC. Some of the pathway inhibitors may also be of importance for nanotherapeutics development. SIGNIFICANCE STATEMENT: This minireview summarizes the progress on chemotherapeutics and nanoparticle delivery for treatment of TNBC and specifically highlights the lead compounds that are in clinical trials.

Combination Nano-Delivery Systems Remodel the Immunosuppressive Tumor Microenvironment for Metastatic Triple-Negative Breast Cancer Therapy.

Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer for which effective therapies are lacking. Targeted remodeling of the immunosuppressive tumor microenvironment (TME) and activation of the body's immune system to fight tumors with well-designed nanoparticles have emerged as pivotal breakthroughs in tumor treatment. To simultaneously remodel the immunosuppressive TME and trigger immune responses, we designed two potential therapeutic nanodelivery systems to inhibit TNBC. First, the bromodomain-containing protein 4 (BRD4) inhibitor JQ1 and the cyclooxygenase-2 (COX-2) inhibitor celecoxib (CXB) were coloaded into chondroitin sulfate (CS) to obtain CS@JQ1/CXB nanoparticles (NPs). Then, the biomimetic nanosystem MM@P3 was prepared by coating branched polymer poly(β-amino ester) self-assembled NPs with melittin embedded macrophage membranes (MM). Both in vitro and in vivo, the CS@JQ1/CXB and MM@P3 NPs showed excellent immune activation efficiencies. Combination treatment exhibited synergistic cytotoxicity, antimigration ability, and apoptosis-inducing and immune activation effects on TNBC cells and effectively suppressed tumor growth and metastasis in TNBC tumor-bearing mice by activating the tumor immune response and inhibiting angiogenesis. In summary, this study offers a novel combinatorial immunotherapeutic strategy for the clinical TNBC treatment.

Abstract 5697: MILIP drives triple-negative breast cancer through complexing with transfer RNAs to promote protein production

Abstract Despite the progress in endocrine therapy, targeted therapy and immunotherapy, the treatment of triple-negative breast cancer (TNBC), one of the most aggressive types of breast cancer, is challenging. This is closely associated with the lack of effective molecular targets in TNBC cells for therapeutic intervention. Here we report that the long noncoding RNA (lncRNA) MILIP drives TNBC cell survival, proliferation and tumorigenicity through complexing with transfer RNAs (tRNAs) to promote protein production, and thus represents a potential therapeutic target in TNBC. MILIP was expressed at high levels in TNBC cells that commonly harbor loss-of-function mutations of the tumor suppressor p53, yet MILIP silencing diminished TNBC cell viability and retarded TNBC xenograft growth, indicating that MILIP functions distinctively in TNBC beyond its well-established role in repressing p53 in other types of cancers. Mechanistical investigations revealed that MILIP interacted with eukaryotic translation elongation factor 1 alpha 1 (eEF1α1) and formed an RNA-RNA duplex with tRNALeu and tRNASer, type II tRNAs, through their variable loops, thus facilitating the binding of eEF1α1 to these tRNAs. Disrupting the interaction between MILIP and eEF1α1 or tRNAs diminished protein production and cell viability, with therapeutic potential revealed where targeting MILIP using Gapmers inhibited TNBC growth and cooperated with the clinically available protein synthesis inhibitor omacetaxine mepesuccinate in vivo. Collectively, these results identified MILIP as an RNA translation elongation factor to promote protein production in TNBC cells and demonstrated that experimental therapy with MILIP Gapmers inhibits TNBC growth, indicating MILIP targeting is a potential avenue for developing improved TNBC treatment through blocking protein synthesis. Citation Format: Yuchen Feng, Simin Zheng, Xiaohong Zhao, Yuanyuan Zhang, Ran Xu, Liang Xu, Thomas Preiss, Lei Jin, Jinnan Gao, Xu Dong Zhang. MILIP drives triple-negative breast cancer through complexing with transfer RNAs to promote protein production [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5697.

Abstract 5935: Non-allosteric inhibition of enolase 1 sensitizes triple-negative breast cancer for checkpoint inhibitors

Abstract Background: Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer that commonly returns and spreads. Currently, very few options are available for TNBC treatment. Cancer cells exploit glycolytic machinery for the Warburg effect and aerobic glycolysis. Enolase 1 (ENO1) is the glycolytic enzyme expressed in most tissues, and many cancer cells have higher expression. Apart from the glycolytic role in the cytosol, ENO1 also plays different roles in cancer cells, including as a surface receptor. Method: non-allosteric chemical inhibition was developed and tested in vitro for its efficacy and target validation. Subsequently, in vivo examinations were conducted on emerging small molecules in syngeneic and patient-derived murine models of breast cancer to unveil their anti-tumor efficacy. Results: Our non-allosteric small molecule inhibitor, SU212, binds to ENO1 and restricts its movement within cells. SU212 treatment leads to the accumulation of ENO1 in the nucleus where it restrains the activity of c-Myc. The treatment causes the production of truncated ENO1 called myc promoter-binding protein 1 (MBP-1), which limits the activity of c-Myc. Stand-alone treatment of SU212 restrains the tumor progression and metastasis in orthotopic syngeneic and PDX mouse models. Combining SU212 and Anti-PD1 significantly inhibits tumor growth and metastasis in mouse models. C-Myc is linked to protein transcription that aids immune resistance and tumor evasion of immune surveillance. Suppression of c-Myc activity via SU212 treatment sensitizes the TNBC tumors for anti-PD1 therapy. Conclusions: This study provides compelling preclinical data for further development of SU0212 as an immune therapy sensitizer for the treatment of TNBC. Citation Format: Dhanir Tailor, Fernando Jose Garcia-Marques, Abel Bermudez, Wenqi Li, Arpit Dheeraj, Sharon J. Pitteri, Sanjay V. Malhotra. Non-allosteric inhibition of enolase 1 sensitizes triple-negative breast cancer for checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5935.

Abstract 6951: The role of estrogen-dependent activation of p38 MAPK signaling pathway in inflammatory breast cancer

Abstract Inflammatory breast cancer (IBC) is a rare and aggressive type of breast cancer in which the lymphatic vessels become blocked by cancer cells in the breast tissue. The five-year survival rate for this type of cancer is around 40%, one of the worst among breast cancer. Most IBCs are estrogen receptor (ER) and progesterone receptor (PR) negative and HER2 positive, with some presenting an amplification of HER2 while others are ER, PR, and HER2 negative, formally known as the triple-negative (TNBC) subtype. However, it has been reported that treatment with 17β-Estradiol (E2) of ER-negative IBC and non-IBC cells can exert rapid non-genomic signaling mediated by ERα-36, GPR30, and/or estrogen receptor beta, activating MAPK pathways involved in oncogenic phenotypes. Previous data generated in our lab showed that when cells were treated with estradiol it led to increased phosphorylation levels of p38. However, the specific role p38 MAPK signaling takes on in IBC is unknown. Thus, this study centers on examining the role of estradiol and p38 regulation in the triple-negative IBC cell line model, SUM149PT. We hypothesize that upon estradiol treatment p38 signaling pathway is activated resulting in the over-expression of pro-inflammatory cytokines which regulate pro-tumorigenic phenotypes including the growth and survival of IBC cells. Inflammatory cytokines can promote pro-oncogenic features by promoting cell proliferation, angiogenesis, and immune suppression. We treated SUM149 IBC cells with 10nM of estradiol and measured the levels of human cytokines using a Human Cytokine Antibody Array. In addition, treatment using SB202190, a potent p38 inhibitor, caused a significant decrease in cell viability of several breast cancer cell lines in a dose-dependent manner. Ongoing studies include assessing the effects of p38 inhibition proliferation, invasion, and migration. In summary, a better characterization of the effect of E2 and p38 activation in ER-negative cell lines may provide great insight into novel targeted therapies for IBC. Citation Format: Keyla V. Ramirez, Adrian D. Bonilla-González, Jeisac Guzman-Rivera, Esther A. Peterson-Peguero. The role of estrogen-dependent activation of p38 MAPK signaling pathway in inflammatory breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6951.

Abstract 6933: Decoding the archetypes and eco-hubs of triple-negative breast cancer in responses to chemotherapy

Abstract Triple-negative breast cancer (TNBC) is a highly aggressive type of breast cancer commonly treated with neoadjuvant chemotherapy (NAC). While about 50% of patients achieve a pathological complete response (pCR), the remainder often develop resistance and metastasis, leading poor survivals. Currently, the factors linking pre-treatment cancer cells and the tumor microenvironment (TME) to NAC response are unclear. To investigate this question, we conducted single-cell RNA sequencing on fresh pre-treatment core biopsy samples collected from patients in the ARTEMIS clinical trial. We identified 13 gene expression meta-programs of cancer cells and about 50 cell states of immune and stromal cell types. Based on the cancer cells alone, we identified four TNBC archetypes at patient-level: luminal secretory-associated (LSA), basal-associated (BA), immunoreactive (IR), and luminal androgen receptor (LAR). Notably, the archetype BA and IR were associated with non-pCR and pCR, respectively. Additionally, we found the TNBC ecosystem was composed of eight eco-hubs, reflecting the co-occurrence patterns of cancer and TME cell states. These eco-hubs revealed different cell community across archetypes and NAC outcomes. For example, an eco-hub with a co-occurrence of interferon response-related cancer cells and immune cells was prevalent in the archetype IR and pCR patients. To facilitate a clinical application, we further developed a 13-gene-based machine learning model to predict NAC response. In summary, these results provide new insights into the cellular determinants of TNBC biology and chemotherapeutic response. Citation Format: Yun Yan, Yiyun Lin, Tapsi Kumar, Shanshan Bai, Jianzhuo Li, Tuan Tran, Min Hu, Elizabeth Ravenberg, Maia Rauch, Alyson Clayborn, Alastair Thompson, Bora Lim, Lei Huo, Stacy Moulder, Clinton Yam, Nicholas Navin. Decoding the archetypes and eco-hubs of triple-negative breast cancer in responses to chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6933.

Abstract 7151: Targeting metabolic pathway in triple negative breast cancer with a small molecule inhibitor

Abstract Background: Triple Negative Breast Cancer (TNBC) is the most aggressive type of breast cancer, making up 15-20% of diagnosed cases, and has high rates of metastasis and recurrence. Most women with this disease experience a recurrence after curative-intent therapy for early breast cancer, while a smaller proportions are diagnosed with distant metastases initially. Cancer cells are characterized by their reprogramming of glucose metabolism. Cancer cells show increased proliferation along with higher energy and substrate demands. Through our efforts to find effective therapies for TNBC, we have identified CET019, a new small molecule that effectively suppresses the growth of breast cancer cells. Methods: Cell viability and clonogenic assays were performed on a range of TNBC cells, including MDA-MB-231, MDA-MB-468, SUM159, HCC1395, HCC1806, EMT6, and 4T1. Cell cycle distribution was assessed through flow cytometry. LC-MS/MS analysis was performed on TMT-labeled samples for global proteome profiling. The efficacy of CET019 (30 mg/kg) was tested using tumor and patient derived xenograft studies. Results: Our studies show that CET019 suppresses the clonogenic potential and growth of various triple-negative breast cancer cells. The CET019 treatment causes cell cycle arrest in TNBC cells at the G2/M phase. Proteomics analysis suggests that CET019 specifically affects metabolic and proteosomal pathways. In vivo studies with CET019 found an inhibition of tumor growth kinetics in the mouse xenograft study with different TNBC models, as compared to the control group. We also observed that CET019 inhibited metastatic lung nodules. The results were further substantiated in three Patient Derived Xenograft (PDX) models. Conclusion: In summary, our study has identified a novel small molecule candidate CET019 as a promising lead candidate for TNBC treatment, paving the way for further development.“The complete chemical structures of the compounds used will be disclosed at the time of presentation at the meeting.” Citation Format: Arpit Dheeraj, Fernando Jose Marques, Dhanir Tailor, Abel Bermudez, Benedikt Grau, Sharon Pitteri, Sanjay V. Malhotra. Targeting metabolic pathway in triple negative breast cancer with a small molecule inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7151.

Abstract 5288: Soy isoflavone genistein reboosts targeted therapy sensitivity in triple negative breast cancer

Abstract Triple-negative breast cancer (TNBC) is a very aggressive type of breast cancer that does not expression important proteins called estrogen, progesterone and HER2. This makes TNBC hard to treat because it does not respond to common targeted treatments. However, recent treatments using the immune system to target key immune proteins such as PD-1 and PD-L1 have been successful in many types of cancer. This form of immunotherapy works by blocking PD-1/PD-L1 pathway and leads to stimulating the body's own immune system to recognize and attack cancer cells, thus providing a potential new treatment option for TNBC patients. Nevertheless, only approximately 30% of TNBC patients may respond to these drugs, suggesting the majority of TNBC patients would not benefit from these innovative immunotherapies. It is believed that low levels of immune cells and PD-L1 expression in tumors are the primary reasons for the lack of response or resistance to anti-PD-1/PD-L1 treatments. The use of nontoxic and healthy food and nutrition to increase treatment response is an emerging field of cancer research. Our studies showed that adding genistein (GE), a bioactive dietary component found in soybean products such as soy milk, soy protein and tofu, could significantly enhance the efficacy of anti-PD-1 immunotherapy in a TNBC mouse model that was previously not responsive to the treatment. Our research also found that soybean GE can increase tumor immune response by significantly recruiting active immune cells into the tumor and increasing PD-L1 expression. Our studies will help to establish a novel nutrition-based intervention targeting TNBC patients who might not qualify for this treatment initially. Eventually, we will develop a novel strategy of administering a tailored dietary plan to resensitize these patients to emerging anti-PD-1/PD-L1 immunotherapies. Citation Format: Taiwo Bankole, Zhenhai Li, Yuanyuan Li. Soy isoflavone genistein reboosts targeted therapy sensitivity in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5288.

Abstract 4529: Characterization of PARP inhibitor combination therapies in triple-negative breast cancer

Abstract Introduction: Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer, with limited targeted treatment options. TNBC patients can, however, benefit from targeted drugs known as Poly (ADP-Ribose) Polymerase inhibitors (PARPi). PARPi disrupt DNA repair pathways by targeting tumors with germline BRCA1/2 mutations (BRCA-MUT) via synthetic lethality and PARP-DNA trapping mechanisms. Only 15-20% of the TNBC patient population are BRCA-MUT and can thus benefit from PARPi. However, preclinical studies and clinical trials have suggested that PARPi can also be effective in BRCA1/2 wild-type (BRCA-WT) cancer cells that have genomic phenotypes similar to BRCA-MUT cells, a phenomenon known as BRCAness. Previously, we used whole transcriptome analysis in a panel of TNBC cell lines to identify a 63-gene signature for BRCAness. The 63-gene signature was shown to predict response to PARPi with an accuracy of 86% in patient-derived xenografts, and was present in 45% of TNBC patients. We hypothesize that targeting genes in this 63-gene signature can enhance the sensitivity of PARPi in BRCA-WT and BRCA-MUT TNBC cells. Our aim is to identify and target genes from this signature that are involved in DNA synthesis and repair pathways, to identify effective combination strategies with PARPi. Methods: Using a PARPi-resistant TNBC cell line, MDAMB231, we carried out an siRNA screen of six genes from the 63-gene signature (BARD1, BUB1, RRM2, FEN1, EXO1, and USP1), chosen based on DNA repair functions and small-molecule inhibitor availability. The gene knockdowns were combined with the application of a potent PARPi, talazoparib, to determine the impact on DNA damage and cell death in TNBC cell lines. We then focused on targeting FEN1 function with the inhibitor LNT1. Using the Chou &amp; Talalay combination index, we combined LNT1 with talazoparib to determine drug synergy in TNBC cell lines. Results: The individual siRNA knockdowns of BARD1, BUB1, FEN1, EXO1, and USP1, in combination with talazoparib, led to increased γ-H2AX and cleaved-caspase 3 levels, indicating augmentation of DNA damage and apoptosis. In particular, the FEN1 inhibitor, LNT1 demonstrated efficacy as a single-agent and synergy in combination with talazoparib in both BRCA-WT and BRCA-MUT TNBC cell lines. Conclusions: The siRNA screens, in combination with talazoparib, show that there are indeed targets within the 63-gene signature that can be used with PARPi that enhance DNA damage and cell death. The drug synergy shown between LNT1 and talazoparib in both BRCA-WT and BRCA-MUT TNBC cells suggests that LNT1 with PARPi could be an effective targeted combination approach, with great potential for TNBC patients. Citation Format: Elicia Fyle, Djihane Abdesselam, Mallory Frederick, Saima N. Hassan. Characterization of PARP inhibitor combination therapies in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4529.

Tumor oxygenation nanoliposomes promote deep photodynamic therapy for triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer and has many characteristics including high metastatic rates, poor overall survival, and low response to traditional chemotherapy. Photodynamic therapy (PDT), emerging as a precise treatment modality, has shown promise in improving the antitumor response. However, it still faces challenges such as limited light penetration depth, rapid oxygen consumption, and inadequate targeting ability. In this study, we developed Rose Bengal (RB, photosensitizer) and oxygen co-loaded CREKA-modified UCNP-based nanoliposomes (CLIP-RB-PFOB@UCNP) for tumor targeting and near-infrared (NIR)-triggered deep and long-lasting PDT. Our results demonstrated that CLIP-RB-PFOB@UCNP effectively targeted and accumulated in tumor tissue through the interaction between CREKA and fibronectin, which is overexpressed in tumor cells. Under NIR irradiation, CLIP-RB-PFOB@UCNP exhibited significant destruction of orthotopic tumors, reduced the level of HIF-1α, and efficiently suppressed lung metastasis in a metastatic TNBC model. In conclusion, this study offers new avenues for improving the therapeutic outcomes of PDT for clinical TNBC treatment.

Improving efficacy of TNBC immunotherapy: based on analysis and subtyping of immune microenvironment.

Triple-negative breast cancer (TNBC) is a highly aggressive type of breast cancer that encompasses several distinct subtypes. Recent advances in immunotherapy offer a promising future for the treatment of these highly heterogeneous and readily metastatic tumors. Despite advancements, the efficacy of immunotherapy remains limited as shown by unimproved efficacy of PD-L1 biomarker and limited patient benefit. To enhance the effectiveness of TNBC immunotherapy, we conducted investigation on the microenvironment, and corresponding therapeutic interventions of TNBC and recommended further investigation into the identification of additional biomarkers that can facilitate the subtyping of TNBC for more targeted therapeutic approaches. TNBC is a highly aggressive subtype with dismal long-term survival due to the lack of opportunities for traditional endocrine and targeted therapies. Recent advances in immunotherapy have shown promise, but response rates can be limited due to the heterogeneous tumor microenvironments and developed therapy resistance, especially in metastatic cases. In this review, we will investigate the tumor microenvironment of TNBC and corresponding therapeutic interventions. We will summarize current subtyping strategies and available biomarkers for TNBC immunotherapy, with a particular emphasis on the need for further research to identify additional prognostic markers and refine tailored therapies for specific TNBC subtypes. These efforts aim to improve treatment sensitivity and ultimately enhance survival outcomes for advanced-stage TNBC patients.

Association Between Sleeping Quality and Risk of Breast Cancer Among Women: A Case-Control Study From Pakistan.

This case-control study investigated the relationship between sleep duration and quality with the occurrence of breast cancer among women, both pre- and post-menopausal, in the northwest Khyber Pakhtunkhwa (KP) region of Pakistan. This case-control research was carried in multiple tertiary care facilities. Newly diagnosed primary breast cancer patients were recruited as cases (n = 408), and 5+years age-matched controls (n = 408) were randomly selected from the general population. Participants completed a Pittsburg sleeping quality index (PSQI) questionnaire that included questions on sleep characteristics. Statistical analysis included independent t-tests to compare mean sleep durations and quality scores between groups, and logistic regression to adjust for potential confounders. Sleep onset latency between cases and controls was not significantly associated with health outcomes, with a P-value of .142. However, sleep duration showed a significant association (P = .049). For sleep duration, the adjusted odds ratio for ≤6h was 1.02 (95% CI: .5-2.1), while for 7-8h the adjusted odds ratio was 1.0 (95% CI: .6-1.6). Self-reported sleep quality did not demonstrate significant associations, with the P-value for "very good" sleep quality being .561. Sleep duration of less than 6h among women with triple-negative breast cancer (TNBC) was found to be strongly associated with a more aggressive type of breast cancer, with an adjusted odds ratio of 1.5 (95% CI: 1.02-2.3, P < .05). This study does not provide evidence to support an association between sleep duration or quality and the risk of breast cancer. However, it reports a significant association, with shorter sleep durations linked to an increased risk particularly in the context of aggressive breast cancer types such as TNBC.