bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PO2-23-11: SMAD4 depletion contributes to endocrine therapy resistance by ERBB signaling in HR+HER2- breast cancer
Authors: Li Kang , Shu Dan , Li Han 
Published: May 2024

Abstract
Objectives: Endocrine therapy resistance is a significant clinical challenge for patients with estrogen receptor (ER)-positive breast cancer. Dysregulation of the ER and ERBB signaling pathways plays a key role in endocrine therapy resistance. However, it is unclear how these pathways are integrated during resistance development. SMAD4 is involved in multiple stages of tumorigenesis, but its role in endocrine resistance development remains elusive. Here, we aimed to investigate the role of SMAD4 in the development of acquired endocrine therapy resistance in ER-positive breast cancer. Methods: CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) screening was conducted to identify genes involved in regulating the sensitivity of T47D cells to 4-hydroxytamoxifen (OHT). Bioinformatics analysis was performed to explore the clinical significance of SMAD4. The differential expression of SMAD4 in cells before and after endocrine treatment was assessed by RT-qPCR and immunoblotting. Loss-/gain-of-function assays were conducted to validate the phenotype. RNA-seq and phenotype rescue experiments were used to explore the underlying mechanisms. Drug combination experiments were performed to assess the therapeutic effect on SMAD4-depleted cells. Results: CRISPR screening identified SMAD4 as a key determinant of endocrine therapy resistance. Bioinformatic analysis showed that SMAD4 expression was downregulated in breast cancer tissues and that low expression was associated with poor patient prognosis. Differential expression analysis after endocrine therapy treatment showed that endocrine therapy downregulated the expression of SMAD4. In vitro and in vivo models further demonstrated that SMAD4 downregulation leads to endocrine therapy resistance. Transcriptome sequencing analysis identified that the ER, ERBB and PI3K/Akt/mTOR signaling pathways were aberrantly activated upon SMAD4 depletion. Further analysis revealed that the PI3K/Akt/mTOR pathway may contribute to the regulation of ERBB on ER signaling to some extent. The aberrant activation of autophagy in phenotype rescue experiments was found to reduce the rescue effect of the combination of 4-hydroxytamoxifen (OHT) and lapatinib (LAPA). Finally, drug combination experiments verified that the combined use of OHT, LAPA and hydroxychloroquine (CQ) produced a synergistic effect in SMAD4-depleted cells. Conclusions: Taken together, our findings demonstrate that SMAD4 plays a crucial role in endocrine therapy resistance and suggest a reasonable treatment strategy for ER-positive breast cancer patients who are resistant to endocrine therapy.
Citation Format: Kang Li, Dan Shu, Han Li. SMAD4 depletion contributes to endocrine therapy resistance by ERBB signaling in HR+HER2- 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 PO2-23-11.
Abstract PO2-24-07: Investigation into potential Estrogen Receptor (ER)-mediated regulation of Phosphoserine Aminotransferase (PSAT1)
Authors: Sumlut Mary , Wittliff James , Clem Brian 
Published: May 2024

Abstract
Breast cancer is one of the leading causes of death among women. Expression of different proteins, such as hormone receptors (HR), are used to classify different types of breast cancer (i.e., HR+BC or triple negative breast cancer (TNBC)). While activation of the estrogen receptor (ER) in HR+BC is known to regulate a vast number of downstream targets in promoting breast cancer, there may be additional ER-regulated processes that are still unknown. The serine synthetic pathway has been demonstrated to be crucial in the proliferation and survival of select subtypes of breast cancer and phosphoserine aminotransferase 1 (PSAT1) is a key regulatory step. Previous studies have demonstrated higher PSAT1 levels in cells lacking ER and we now show a negative correlation between ERα protein levels and PSAT1 transcripts in human patient samples. This indicates that ER may potentially regulate PSAT1 expression. To initially investigate this potential relationship, either WT or constitutively active mutant ERα was expressed in TNBC cells (MDA-MB-231), which have high endogenous PSAT1 expression and no ER. Immunoblot was used to verify ERα levels and to assess effects on PSAT1. We observed a qualitative trend in decreasing PSAT1 levels with re-expression of ERα in the TNBC cells. While the variabilities in these results preclude any conclusion of a ERα:PSAT1 regulatory axis, the lack of a quantifiable effect on PSAT1 levels is postulated to be due to the transient nature of ERα expression/suppression in these systems. A more profound effect would be expected under durable changes in ERα levels and is a focus on-going studies.
Citation Format: Mary Sumlut, James Wittliff, Brian Clem. Investigation into potential Estrogen Receptor (ER)-mediated regulation of Phosphoserine Aminotransferase (PSAT1) [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 PO2-24-07.
Abstract PO2-28-03: E-Cigarette Aerosol Exposure: Unraveling the Nexus of Autophagy, Cancer Stem Cells, and EMT in Breast Cancer Metastasis
Authors: Thota Shilpa , Begum Rizwana , Chintalaramulu Naveen , Sapkota Biplov , Pandit Abhishek 
Published: May 2024

Abstract
Electronic cigarettes (E-cigs) have emerged as a significant public health concern due to their increasing popularity. These products have been associated with various harmful effects on human health. In the United States, breast cancer is the most diagnosed cancer among women, and its recurrence and metastasis are primary contributors to morbidity and mortality. Two critical factors in cancer progression are Epithelial-mesenchymal transition (EMT) and Cancer stem-like cells (CSCs), both of which play pivotal roles in metastasis. As a result, targeting the signaling pathways involved in these processes has become a promising avenue for cancer therapy. Autophagy, a cellular process, has dual roles in cancer development depending on the cancer type and stage. Given these considerations, our hypothesis centers on disrupting the EMT-mediated metastatic cascade in breast cancer by targeting autophagy in Cancer Stem Cells (CSCs). To investigate this hypothesis, we conducted experiments using mouse breast epithelial cells (HC11) and Triple-negative mouse breast cancer cells (4T1) exposed to E-cig aerosol at the air-liquid interphase (ALI) for 1 hr followed by a 24 hr recovery period. Our findings indicate that exposure to E-cig aerosols led to a decrease in epithelial markers (E-Cadherin and β-catenin) and an increase in mesenchymal markers (N-Cadherin and Vimentin) in HC11 cells. This suggests that normal cells may acquire characteristics associated with solitary migration. Furthermore, we observed significant changes in the levels of autophagy-related proteins (LC3B, Beclin-1, ATG12, and ATG16) and upregulation of stem cell markers (OCT4, SOX2, NANOG, KLF4, and c-MYC) in response to E-cig aerosol exposure, both in HC11 and 4T1 cells. Additionally, these alterations extended to changes in the expression of genes associated with the Transforming Growth Factor-beta (TGF-β) signaling pathway, known to play a potential role in promoting EMT. Our results provide a deeper understanding of the interplay between EMT, CSCs, and the autophagy process in the context of ALI exposure in normal and cancer cells. This underscores the need for further research into the shared molecular mechanisms of these three processes to identify common therapeutic targets that can simultaneously affect them.
Citation Format: Shilpa Thota, Rizwana Begum, Naveen Chintalaramulu, Biplov Sapkota, Abhishek Pandit. E-Cigarette Aerosol Exposure: Unraveling the Nexus of Autophagy, Cancer Stem Cells, and EMT in Breast Cancer Metastasis [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 PO2-28-03.
Abstract PO3-01-11: Clinical Significance of HER2-low Breast Cancer
Authors: Zaiem Fadi , AbuJamea Asem , Kheil Mira , Numi Anna , Abbas Omar , Awada Sanaa , Almsaddi Ragad , Al-Juburi Saleh , Larson Lauren , Jain Deepti , AlSaghir Maya , Jang Hyejeong , Kim Seongho , Bandyopadhyay Sudeshna , Jaiman Sunil , Ali-Fehmi Rouba 
Published: May 2024

Abstract
Context: Breast cancers with a HER2 immunohistochemistry (IHC) result of 1+ or 2+ and a negative amplification test (FISH), previously treated as HER2 negative, are now termed HER2-low and are being targeted for treatment. We aim to explore the clinical significance of this group. Design: 394 breast cancer cases were included from our institution from 2010. Demographic and clinicopathological data on receptors status, recurrence/metastasis, treatment, and survival was collected. HER2 was re-evaluated according to the 2018 CAP ASCO guidelines and patients were treated according to standardized protocol. HER2 +2 with positive FISH and HER2 +3 were excluded. HER2-low was compared to HER2-0. Appropriate statistical analysis was performed. Results: 394 patients (76% IDC; 8% ILC; 16% others) were included, such that 91 (23%) were HER2-0 and 303 (77%) HER2-low. Median age was 58 years (range: 25-95). Median follow-up was 54 months (range: 0.5-259). Grade 3 tumors were significantly more frequent in HER2-0 than HER-2 low (52% vs. 33%; p=0.010). Grade 3 or ILC patients had higher risk of recurrence than Grade 1 (HR 2.55; p&lt; 0.001) or IDC (HR 2.03; p=0.033). After adjusting for grade, HER2-low had a significantly worse RFS than HER2-0 (HR 1.58; p=0.043). In the ER negative subgroup, HER2-low had significantly worse RFS than HER2-0 (HR 2.02; p=0.023). No differences in overall survival were seen. Conclusions: Our data showed higher recurrence in HER2-low group compared to HER2-0. This suggests that breast cancer patients with HER2- low are a separate entity and might benefit from additional targeted therapy.
Table 1 Hazard regression analysis of risk factors associated with recurrence
Citation Format: Fadi Zaiem, Asem AbuJamea, Mira Kheil, Anna Numi, Omar Abbas, Sanaa Awada, Ragad Almsaddi, Saleh Al-Juburi, Lauren Larson, Deepti Jain, Maya AlSaghir, Hyejeong Jang, Seongho Kim, Sudeshna Bandyopadhyay, Sunil Jaiman, Rouba Ali-Fehmi. Clinical Significance of HER2-low 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 PO3-01-11.
Abstract PO3-04-09: Prognoses of Patients with Hormone Receptor-Positive andHuman Epidermal Growth Factor Receptor 2-Negative BreastCancer Receiving Neoadjuvant Chemotherapy before Surgery:A Retrospective Analysis
Authors: Zhang Jin , Liu Yan , Zhang Shichao 
Published: May 2024

Abstract
Abstract: Purpose: To evaluate the clinical characteristics, pathological response, and prognostic significance of hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2−) breast cancer (BC) after neoadjuvant chemotherapy (NAC). Methods: A survival analysis was performed to detect the factors related to recurrence and death in 3070 consecutive patients with HR+/HER2− BC who received NAC from 2011 to 2022. All patients received current “standard of care” following neoadjuvant therapy based on guidelines, including surgery and adjuvant endocrine therapy. HER2-low was defined as immunohistochemistry (IHC) 1+ or IHC 2+ and fluorescence in-situ hybridization-negative. Results: The complete pathological response (pCR) (ypT0/is ypN0) rate was 14.5%. The clinical tumor size (cT), ER scores, PR status, and Ki67 levels were related to pCR. The 5-year disease-free survival (DFS) and overall survival (OS) rates were 82.6% and 90.4%, respectively. PR, Ki67 levels, and postmastectomy radiotherapy were independent factors for DFS and OS, and the extranodal extension (ENE) correlated with DFS. However, pCR and HER2 status were related to OS. The pCR rate in PR negativity BC was significantly higher than that in PR positivity BC (21.1% vs. 12.2%, p = 0.000), but PR negativity BC had a poorer prognosis than PR positivity BC. HER2-low BC showed high ER scores (over 50%), PR positivity, large ypT, ENE, and lymphovascular invasion but a lower pCR rate than HER2-zero BC. Patients with HER2-low BC had shorter OS than those with HER2-zero BC (p = 0.037). However, there was no difference in DFS. Conclusions: Depending on PR status and HER2 status, patients with ER positivity and HER2 negativity exhibit different pathologic complete response rates to neoadjuvant chemotherapy and long-term outcomes, especially patients with PR negativity or HER2-low status. Keywords: breast cancer; neoadjuvant chemotherapy; survival; prognosis; PR; HER2-low
Citation Format: Jin Zhang, Yan Liu, Shichao Zhang. Prognoses of Patients with Hormone Receptor-Positive andHuman Epidermal Growth Factor Receptor 2-Negative BreastCancer Receiving Neoadjuvant Chemotherapy before Surgery:A Retrospective Analysis [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 PO3-04-09.
Abstract PO3-09-12: Exploring Gender-Specific Patterns of Breast Cancer in Brazil: A Comparative Epidemiological Study
Authors: Antonini Marcelo , Pannain Gabriel , Buttenbender Steffi , Mattar Andre , Lopes Reginaldo Coelho , Ferraro Odair 
Published: May 2024

Abstract
Introduction: Male breast cancer constitutes approximately 1% of all breast cancer cases, and limited studies have focused on this population, resulting in a lack of understanding of the disease in men. This study aims to describe the epidemiological profile of male breast cancer in Brazil and compare it with female breast cancer. Methods: A comprehensive observational cross-sectional study was conducted using retrospective data from the DATASUS database (SISCAN/Cancer Information System) spanning the period from 2017 to 2021. Male and female patients diagnosed with breast cancer (ICD C50) during this period were included. Statistical analysis involved absolute values, percentages, and a 95% confidence interval (p &lt; 0.05). Results: Analysis of the study period revealed 4,326 cases (1.8%) of male breast cancer and 236,597 cases (98.2%) of female breast cancer in Brazil. The southeast region had the highest concentration of cases for both sexes, while the northeast region showed a higher prevalence in males (p &lt; 0.0004). Noteworthy findings include a higher mean age among males (59.5 years) compared to females (55.7 years) and a higher prevalence of advanced stages at diagnosis in males (72.8% vs. 59.3%). Diagnostic approaches, subtype distribution, and treatment modalities also differed between the genders. Conclusions: Male breast cancer presents with more advanced stages at diagnosis compared to females, necessitating more aggressive surgical interventions. However, males benefit from earlier initiation of treatment. These findings contribute to a better understanding of male breast cancer, enabling the development of tailored management strategies for this unique patient population.
Comparison between male and female MC
XX XX Source: Panel-Oncology Brazil (accessed 15/04/2023)
Citation Format: Marcelo Antonini, Gabriel Pannain, Steffi Buttenbender, Andre Mattar, Reginaldo Coelho Lopes, Odair Ferraro. Exploring Gender-Specific Patterns of Breast Cancer in Brazil: A Comparative Epidemiological 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 PO3-09-12.
Abstract PO3-12-02: SAFETY AND TOLERANCE OF THE USE OF SHOCK WAVE THERAPY IN LYMPHEDEMA SECONDARY TO THE TREATMENT OF BREAST CANCER
Authors: Ventura Patricia Lima , Haddad Cinira , Sanvido Vanessa , Nazário Afonso , Facina Gil , Estevao Amanda , Rizzi Samantha Lopes de Almeida 
Published: May 2024

Abstract
Introduction: Lymphedema is a very common complication of breast cancer treatment. The first-line therapeutic method for lymphedema is Complex Physical Therapy. An option currently mentioned as an adjuvant and non-invasive treatment for lymphedema secondary to breast cancer is Shockwave Therapy. Objectives: To evaluate the safety and tolerance of shockwave therapy for the treatment of upper limb lymphedema secondary to breast cancer treatment. Methods: This is a quasi-experimental study carried out with 17 women who underwent breast surgery associated with axillary lymphadenectomy or Sentinel Lymph Node Biopsy and who had upper limb lymphedema secondary to the treatment of breast cancer. All were treated with complex physical therapy prior to the study. Four sessions of Shockwave Therapy were applied, 4000 shocks at 0.06 mJ/mm2, 1 time per week for 4 consecutive weeks. For that, the participants were evaluated through the application of questionnaires and physical examination and underwent shock wave therapy for the upper limb ipsilateral to the surgery. Results: After the intervention, none of the participants had skin lesions, blisters, desquamation or hyperthermia of the limbs, and 17.65% had skin redness. Most patients reported no change in their social life and that they felt safer in daily activities and very satisfied with the treatment. The patients showed improvement in upper limb functionality after the intervention versus baseline (p=0.02). No difference in limb volume and shoulder range of motion over time for all movements performed was found after the intervention and at the evaluated intervals. In addition, improvements were observed in some domains of the quality-of-life questionnaires. Conclusion: Shockwave Therapy proved to be safe and tolerable in patients with lymphedema, with improved functionality and no significant change in the volume of the affected limb. Keywords: Extracorporeal shock wave therapy; Lymphedema; Breast cancer.
Citation Format: Patricia Lima Ventura, Cinira Haddad, Vanessa Sanvido, Afonso Nazário, Gil Facina, Amanda Estevao, Samantha Lopes de Almeida Rizzi. SAFETY AND TOLERANCE OF THE USE OF SHOCK WAVE THERAPY IN LYMPHEDEMA SECONDARY TO THE TREATMENT OF 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 PO3-12-02.
Abstract PO3-15-06: Identification of a Novel Five Ferroptosis-Related Gene Signature as a Promising Prognostic Model for Breast Cancer
Authors: Cheng Tian-cheng , Wu Jia-hao , Zhu Bei , Zheng Lin , Chen Wei-xian 
Published: May 2024

Abstract
Background: Breast cancer (BCa) is a major challenge for women's health worldwide. Ferroptosis is closely related to tumorigenesis and cancer progression. However, the prognostic value of ferroptosis-related genes in BCa remains unclear, and more accurate prognostic models are urgently needed. Methods: Gene expression profiles and clinical information of BCa patients were collected from public databases. LASSO and multivariate Cox regression analysis were utilized to construct the prognostic gene signature. Kaplan-Meier plotter, Receiver Operating Characteristic (ROC) curves, and nomogram were used to validate the prognostic value of the gene signature. Gene set enrichment analysis was performed to explore the molecular functions and signaling pathways. Results: Differentially expressed ferroptosis-related genes between BCa samples and normal tissues were obtained. A novel five-gene signature including BCL2, SLC40A1, TFF1, APOOL, and PRAME was established for prognosis prediction. Patients stratified into high-risk or low-risk group displayed significantly different survival. Kaplan-Meier and ROC curves showed a good performance for survival prediction in different cohorts. Biological function analysis revealed that the five-gene signature was associated with cancer progression, immune infiltration, immune response, and drug resistance. Nomogram including the five-gene signature was established. Conclusions: A novel five ferroptosis-related gene signature and nomogram could be used for prognostic prediction in BCa. Key words: breast cancer, ferroptosis, gene signature, overall survival, prognosis
Citation Format: Tian-cheng Cheng, Jia-hao Wu, Bei Zhu, Lin Zheng, Wei-xian Chen. Identification of a Novel Five Ferroptosis-Related Gene Signature as a Promising Prognostic Model for 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 PO3-15-06.
Abstract PO3-16-04: Distribution of intrinsic subtypes in endocrine-resistant and endocrine-sensitive breast cancer
Authors: Schagerholm Caroline , Robertson Stephanie , Karlsson Emelie , Sifakis Emmanouil , Hartman Johan 
Published: May 2024

Abstract
Background
Breast cancer (BC) is a heterogeneous disease that can be divided into intrinsic molecular subtypes. Among the four intrinsic subtypes, Luminal A and Luminal B are the most common and associated with the best outcome, whereas HER2-enriched and basal-like are less frequent. Tumors that are estrogen receptor α (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative (ER+/HER2-) are mostly found among the luminal subtypes. Despite that patients with ER+/HER2- tumors are offered adjuvant endocrine therapy, around one-third eventually develop endocrine resistance. The aim of this study was to explore the distribution of intrinsic subtypes in endocrine-resistant primary and relapse tumors, comparing these to endocrine-sensitive controls.
Materials and methods
Verified endocrine-resistant BC patients diagnosed in 2008-2012 were retrospectively collected at the Karolinska University Hospital, Stockholm, Sweden. Cases (N=70) were identified as patients with ER+/HER2- primary tumors and subsequent ER+/HER2- relapse tumors within 5 years and during endocrine therapy. Patients with primary ER+/HER2- tumors without progression or relapse at 10 years of follow-up were defined as controls (N=78), diagnosed in 2005-2006. Extracted RNA from formalin-fixed paraffin-embedded tumor tissue was analyzed by Affymetrix Clariom D Microarray and assessed by Transcriptome Analysis Console and R software.
Results
Among the controls, the distribution of Luminal A, Luminal B, and HER2-enriched subtypes was 65.4%, 34.6%, and 0%, respectively. In primary tumors, the distribution was in turn 55.4%, 43.1%, and 1.5%, and among relapse tumors 57.6%, 37.9%, and 4.5%, respectively. A total of 19 cases, accounting for 27.1%, switched intrinsic subtypes between the paired primary and relapse tumors. No tumors exhibited the basal-like subtype.
Conclusion
In this unique cohort, Luminal B and HER2-enriched subtypes were more common in primary and relapse tumors of verified endocrine-resistant patients than in primary tumors of endocrine-sensitive controls. Further, the HER2-enriched subtype, although sparse, was more frequently found in patients’ relapse tumors than in their corresponding primary tumors, and over one-fourth of cases switched subtypes during progression. These findings support the presence of subtype shifting in endocrine-resistant relapses and that endocrine-resistant tumors are more prone to be of Luminal B or HER2-enriched subtypes than endocrine-sensitive tumors.
Citation Format: Caroline Schagerholm, Stephanie Robertson, Emelie Karlsson, Emmanouil Sifakis, Johan Hartman. Distribution of intrinsic subtypes in endocrine-resistant and endocrine-sensitive 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 PO3-16-04.