bluuebunny/crossref_metadata_2025_split huggingface dataset:
ODP562 ZnT5 Involvement in EMT in Breast Cancer
Authors: Miki Yasuhiro , Iwabuchi Erina , Xu Junyao , Ishida Takanori , Sasano Hironobu 
Published: November 2022

Abstract
The zinc levels in breast cancer tissue are reportedly higher than in normal tissue. In addition, the expression levels of zinc transporters, including ZnT5 and ZnT6, in breast cancer tissue are higher than in normal breast tissue. Moreover, ZnT5 and ZnT6 contribute to the formation of heterodimers and are involved in different biological functions. In vitro studies using chicken DT40 cells showed that ZnT5 and ZnT6 heterodimers are required to activate several proteins that play important roles in tumorigenesis, infiltration, and metastasis. However, the functions of ZnT5 and ZnT6 heterodimers in breast cancer remain unknown. Therefore, in this study, we first immunolocalized ZnT5 and ZnT6 in 113 pathological specimens of breast cancer. We then analyzed the interaction between ZnT5 and ZnT6 in breast cancer tissue using proximity ligation assay (PLA). Further, we evaluated cell migration and the expression of epithelial mesenchymal transition (EMT) markers as well as vimentin and E-cadherin in ZnT5 knockdown MCF-7 cells using siRNA. Next, we utilized human phosphorylation multipathway profiling array to explore the underlying mechanism of ZnT5 knockdown-induced cell migration. Immunohistochemical analysis revealed that the number of ZnT5-positive breast cancer cells was significantly higher in patients with a low pathologic N factor, and the number of ZnT6-positive breast cancer cells was significantly higher in patients with a low histological grade. The number of ZnT5 and ZnT6 double-positive breast cancer cells was significantly higher in patients with low Ki-67 expression than those with ZnT5-positive and ZnT6-negative breast cancer cells. In addition, ZnT5 and ZnT6 heterodimers were detected using PLA in breast cancer tissues with high expression of both ZnT5 and ZnT6. Treatment with 100 µM ZnCl 2 inhibited migration of MCF-7 cells, but ZnT5 knockdown promoted cell migration. ZnT5 knockdown induced higher levels of vimentin and lower levels of E-cadherin and activated SMAD1 in the presence of 100 µM ZnCl 2 . These results indicate that the involvement of ZnT5 in the inhibition of EMT through SMAD1 inactivation. These results also indicate that the role of ZnT5 and ZnT6 heterodimers differs from that of the ZnT5 homodimer in cell proliferation. However, further studies are required to clarify the role of zinc transporters and zinc signaling in breast cancer.
Presentation: No date and time listed
ODP647 Nuclear ERα and NAMPT Crosstalk in Metastatic Breast Tumors
Authors: Mogol Ayca , Chien Christine , Zuo Qianying , Singareeka Raghavendra Akshara , Tripathy Debu , Landesman Yosef , Madak-Erdogan Zeynep 
Published: November 2022

Abstract
Approximately 70% of human breast cancers express estrogen receptor alpha (ERα), providing a potential for targeted endocrine therapy for patients. Unfortunately, 30-40% of ER+ patients still experience recurrence and metastasis, with a 5-year relative overall survival rate of just 24% for patients with metastatic disease. Previously, we described an increased reliance on NAD+ metabolism in metastatic breast cancer (MBC) cells, which are driven by clonal selection from monotherapy resistance and the metastatic organ microenvironment. In the current study, we investigated if inhibition of NAMPT to block NAD+ production would synergize with standard of care therapies for ER+ MBC. Combination therapy of the NAMPT Inhibitor, KPT9274 and the ERα agonist Fulvestrant (Fulv) synergistically reduced tumor burden in liver metastasis in vitro (combination index &lt; 1 in cell viability assays) and in vivo in mouse xenograft models. A synergistic effect was not observed when KPT-9274 was combined with Palbociclib or Tamoxifen, nor Fulv with other metabolic inhibitors. RNA-Seq analysis showed that NAMPT inhibition restored antiestrogenic activity of Fulv. Metabolomics analysis showed that NAMPT inhibition reduced abundance of metabolites associated with glucose and lipid metabolism. Mechanistically, chromatin immunoprecipitation showed that NAMPT is recruited to ERα binding sites in MBC xenografts and PDX tumors. Targeting metabolic adaptations in endocrine-resistant metastatic breast tumors is a novel approach that could lead to new combined therapies that reduce mortality.
Presentation: No date and time listed
OR16-1 How Strong and Sustained Activation of the Estrogen Receptor-mediated Anticipatory Unfolded Protein Response Kills Breast and Ovarian Cancer Cells
Authors: Boudreau Matthew , Duraki Darjan , Hergenrother Paul , Kim Ji Eun , Livezey Mara , Nelson Erik , Park Ben H , Shapiro David , Yang Rachel , Ghosh Santanu 
Published: November 2022

Abstract
In orthotopic xenografts and a PDX, our anticancer drug ErSO eradicates primary and metastatic therapy-resistant estrogen receptor alpha (ERα) positive breast cancer, and induces near-complete regression of ovarian cancer. The mechanism by which ErSO induces necrosis and kills ER positive cancer cells was unknown. From genome-wide CRISPR-Cas9 screens in MCF-7 and T47D cells with negative selection against first-generation BHPI and second-generation ErSO, and follow-on experiments, we identified the Ca2+ activated, plasma membrane Na+ channel TRPM4 as the executioner protein that BHPI and ErSO use to induce necrosis. Notably, in 6 ERα+ breast and ovarian cancer cell lines, knockout of TRPM4 completely abolished the ability of ErSO to induce death of cancer cells. Moreover, TRPM4 mRNA and protein were dramatically down-regulated in breast cancer cells selected for resistance to BHPI and ErSO. Furthermore, in a mouse xenograft, while ErSO induced near complete regression of orthotopic MCF-7-ERY537S-luciferase tumors, ErSO had no effect on the TRPM4 knockout tumors, which continued their robust growth. Since necrosis, but not most other death pathways, activates immune cells, inducing immunogenic cell death, this provides a new avenue for enhancing cancer immunotherapy. Importantly, medium from ErSO-treated wild type MCF-7 cells, but not medium from TRPM4 knockout cells, robustly activates human THP-1 monocytes and greatly increases their migration. BHPI and ErSO-induced initial anticipatory unfolded protein response (a-UPR) activation results in elevated cytosolic Ca2+, opening the plasma membrane TRPM4 channel, eliciting a rapid influx of external Na+, accompanying Cl- to balance the charge, and water to maintain osmolality. This swells the cells, causing osmotic stress. Importantly, it is the osmotic stress that sustains UPR hyperactivation, leading to ATP depletion, which contributes to membrane rupture and rapid necrotic cell death and to near complete inhibition of protein synthesis that ultimately kills any surviving cancer cells . Suggesting a broad role of TRPM4 in the actions of necrosis inducing anticancer drugs, TRPM4 knockout also inhibited necrosis induced by unrelated anticancer therapies, the mitochondrial targeting oncolytic peptide, LTX-315 and the Ca2+ channel targeting agent, Englerin A. Since increasing expression TRPM4 by viral transduction results in progressively increased sensitivity of ER positive breast cancer cells to killing by ErSO, this enables identification of breast cancer patients whose elevated TRPM4 levels make them most likely to benefit from this novel therapy. The TRPM4 pathway is a new mechanism for sustained lethal activation of the UPR and for targeting ER positive breast and ovarian cancer.
Presentation: Sunday, June 12, 2022 11:00 a.m. - 11:15 p.m.
OR30-4 Role of ABCA1 in Myeloid Cell Function and Breast Cancer Progression
Authors: Cho Wonhwa , Krawczynska Natalia , Nelson Erik R , Singaram Indira , Bendre Shruti 
Published: November 2022

Abstract
Breast cancer is the second leading cause of cancer related deaths in women in the United States, with most mortalities associated with recurrent metastasis. Interestingly, high cholesterol levels are associated with an increased risk of breast cancer recurrence and poor prognosis, while therapies that lower cholesterol concentrations are associated with a good prognosis. Previous work has identified a metabolite of cholesterol, 27-Hydroxycholesterol (27HC), as being able to promote the progression and metastasis of breast cancer. 27HC does so by acting on myeloid immune cells. Within the tumor microenvironment, macrophages are abundant cells in the myeloid lineage. When macrophages were treated with 27HC, their ability to activate T cells was impaired. Those T cells that were activated, had a decreased anti-cancer cytotoxic response. Subsequent work has identified the Liver×Receptor (LXR) as mediating the immune-suppressive effects of 27HC. However, the mechanism by which LXR activity within myeloid cells inhibits subsequent T cell activity is unknown.ABCA1 is a classic target gene of LXR and is known to facilitate cholesterol efflux from the cell. Our analysis of publicly available transcriptome indicates that ABCA1 expression within breast tumors is associated with good prognosis. These somewhat paradoxical observations suggest that ABCA1 exhibits a pro-immune and anti-cancer effect – opposite to what we would expect for LXR activation. Therefore, the goal of the current work is to determine the effect of manipulation of ABCA1 within macrophages and its consequent effect on T cells in vitro and in context to breast cancer metastasis. Our results to date indicate that knocking down ABCA1 using siRNA by targeting the 3' UTR decreased the expression of genes associated with macrophage function and interaction with T cells. Importantly, many of those effects were rescued by over- expression of ABCA1.In summary, our results indicate that although ABCA1 is a target gene of LXR, the induction of ABCA1 by LXR may be compensatory rather than driving the immunosuppressive effects of 27HC. Thus, we hypothesize that ABCA1 plays a pro-immune function and could be a potential therapeutic target to boost the immune system.
Presentation: Tuesday, June 14, 2022 10:30 a.m. - 10:45 a.m.
PSUN347 A Novel Mechanism-based Inhibitor of Ribonucleotide Reductase is Highly Effective in Preclinical Models of Endocrine Therapy-Resistant Breast Cancer
Authors: Dealwis Chris , Keri Ruth , Weber-Bonk Kristen , Baker Taylor 
Published: November 2022

Abstract
Approximately 70% of breast cancers express Estrogen Receptor (ER), and patients with ER+ disease benefit from first-line targeted anti-hormone therapies (e. g. tamoxifen). However, at least 30% of patients develop therapeutic resistance. Second-line therapy includes CDK4/6 inhibitors, yet patients nearly uniformly develop resistance to these drugs as well, highlighting the need to identify additional targets in resistant tumors. In this regard, tamoxifen-resistant breast cancer cells and tumors display increased expression of several key cell cycle and chromosomal maintenance-related genes. This includes elevated expression of genes in the Chromosomal Instability (CIN70) signature, comprising of 70 genes that promote CIN and facilitate tumor progression. RRM2 is one such gene that encodes the small subunit of Ribonucleotide Reductase (RNR). In public RNA-seq data, RRM2 was one of the most differentially expressed CIN70 genes in tamoxifen-resistant cells and tumors, and increased expression is associated with poor patient outcomes. We hypothesized that elevated RRM2 drives CIN and subsequent tamoxifen resistance, and that targeting RRM2 or RNR activity will exacerbate CIN to intolerable levels, leading to drug-resensitization and cell death. We confirmed that RRM2 expression is elevated in multiple tamoxifen-resistant ER+ breast cancer cell lines compared to their parental counterparts. Moreover, we found that tamoxifen-resistant cells also exhibit increased CIN phenotypes as indicated by nuclear defects (micro-, multi-, and dysmorphic nuclei). As a model of intrinsic resistance to endocrine therapy, we examined RRM2 expression in triple-negative breast cancer (TNBC) cells that lack ER and found that these cells also have elevated RRM2 compared to ER+ cells. These data affirm the utility of targeting RNR for treating aggressive disease. While there are five currently approved RNR inhibitors, they cause significant patient toxicities due to their chelator mechanism of action. To address this limitation, we developed a novel mechanism-based inhibitor of the catalytic activity of RNR (RRM127) that is less toxic in mouse models. We demonstrate that RRM127 induces excessive CIN in breast cancer cell lines with high RRM2 expression. Most importantly, we have found that RRM127 suppresses growth of both cell line and patient-derived TNBC xenografts in mice. Together, these results indicate that elevated RRM2 and its associated RNR activity promote CIN and that catalytic inhibition with RRM127 has strong efficacy in preclinical models of breast cancer. Current studies are focused on identifying the mechanisms by which RRM127 blocks breast cancer cell growth.
Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
PSUN378 A Turducken Phenomenon: A Case of Papillary Thyroid Carcinoma Arising Within Struma Ovarii Associated With a Large Mucinous Cystadenoma
Authors: Ali Israa , Khan-Atif Sara , Shah Nisarg 
Published: November 2022

Abstract

Introduction
Struma Ovarii (SO) is one of the types of mature teratoma accounting for up to 3% of all ovarian tumors, with predominant thyroid tissue (&gt;50%). Most cases are reported in middle-aged women. We are presenting a case of asymptomatic papillary thyroid cancer (PTC) presented in SO that was incidentally found and treated successfully

Case presentation
A 72-year-old Hispanic female with a history of hysterectomy, tobacco smoking was found to have a suspicious lung nodule on screening with CT scan of Chest. A subsequent PET/CT Scan revealed incidental findings of left adnexal lesion of 12×12 cm with no FDG uptake and had a minimal uptake in lung nodule favoring a hamartoma. At the gynecology clinic, patient denied having vaginal bleeding, bowel dysfunction, abdominal pain or weight loss. She did report urinary incontinence. Pelvic exam demonstrated a mobile left adnexal mass without tenderness. MRI of Pelvis revealed a 15 cm multi-cystic, left ovarian mass compressing the urinary bladder without any lymphadenopathy.
Tumor markers of CEA and CA-125 were normal. The patient underwent bilateral salpingo-oophorectomy with extensive adhesolysis. Entire ovarian mass was removed intact. Surgical Pathology revealed a 1.2 cm Unifocal PTC arising in 3 cm SO associated with mucinous cystadenoma without lympho-vascular invasion and extra-ovarian extension. No malignant cells were identified in peritoneal washing. This was staged according to AJCC 8th edition as pT1aNxMna. Immunostaining of TTF-1 and TG were positive, which additionally supported above diagnosis. Mutational testing of BRAF, K-RAS and N-RAS were negative.
Post-operatively, at the Endocrine clinic, her TSH and Free T4 were normal. No nodules were detected on the thyroid ultrasound. She was deemed low risk for recurrence and no further treatment was advised except serial monitoring of Thyroglobulin levels and goal TSH &lt; 2.5 mIU/L.

Discussion
In general, SO can be diagnosed only on a histopathological specimen and no specific radiological or biomarkers are available. Most patients are euthyroid and remain asymptomatic like our patient. Thyrotoxicosis occurs in only 5–15% of patients. SO is mostly benign. Its malignant transformation occurs in only 5% of all cases. The most widespread malignant forms of SO are papillary and follicular carcinomas.
There are no well-established guidelines for optimal management of malignant SO. After undergoing oophorectomy, the decision to perform a prophylactic thyroidectomy and administration of 131I-Radioiodine is typically reserved for presence of metastatic disease or high risk of recurrence (&gt;4 cm tumor size, gross extra-ovarian extension, BRAF positivity or histology other than papillary type).
Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
RF05 | PSUN365 Insulinoma: A Case Report of a Rare Functioning Neuroendocrine Tumor
Authors: Pescador Antonio , Rosario Michael 
Published: November 2022

Abstract

Insulinoma is a rare functional neuroendocrine tumor that causes inappropriate release of insulin, resulting in symptoms of hypoglycemia which would resolve promptly following glucose administraton. Its incidence is 1 to 3 per 1,000,000 population per year.

Case presentation
This study reports on a 64 year old female with no known co-morbidities who was seen in the endocrinology clinic due to episodes of blurring of vision, lightheadedness and shakiness. Glucose levels as low as 40mg/dL were detected with glucometer during these episodes. Symptom would improve after eating carbohydrate rich food. Symptom onset was 4 years prior to consult. Patient also reported weight gain as she would over-eat to treat her symptoms. The patient came in for evaluation and management of Hypoglycemia. Blood tests revealed high insulin (146.60 uU/mL; reference range: 5.00–10.00 uU/mL) and C-peptide level (7.45 ng/mL; reference range: 0.78–5.19 ng/mL) despite low plasma glucose level (36 mg/dL). Dynamic CT scan of the pancreas revealed an arterially enhancing nodule with intralesional calcification in the distal pancreatic body for which an insulinoma is considered. She underwent distal pancreatectomy and her symptoms showed complete resolution. Surgical pathology was consistent with well differentiated Neuroendocrine tumor.

Conclusion
Clinicians should have a high index of suspicion for Insulinoma in patients with history of recurrent episodes of blurring of vision, lightheadedness and shakiness, particularly if these symptoms would resolve after food intake. Such condition entails proper and timely diagnosis, localization of the tumor and treatment and involves several specialties.
Presentation: Saturday, June 11, 2022 1:36 p.m. - 1:41 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
RF07 | PSUN350 Estradiol Effects on Polymorphonuclear Cell Production and Actions Contribute to Estrogen-mediated Lymphangioleiomyomatosis (LAM) Progression
Authors: Minor Briaunna , LeMoine Dana , Seger Christina , Gibbons Erin , Koudouvoh Jules , Hammes Stephen 
Published: November 2022

Abstract
Lymphangioleiomyomatosis (LAM) is a rare lung disease seen almost exclusively in female sexed individuals and characterized by slowly growing, metastatic smooth muscle cell-like adenomas that cause cyst formation in the lung parenchyma and irreversible loss of pulmonary function. Given the female specificity of disease manifestation, metastatic nature, and estrogen sensitivity of LAM cells, we previously proposed that LAM cells originate in the myometrium. Our subsequent reports showed that inactivation of TSC2 in the mouse uterus results in notable LAM features in the setting of primary myometrial tumors. Additionally, we established that estrogen is required to maintain LAM-like tumor progression in a uterine-specific Tsc2-knockout murine model. However, the observed estrogen sensitivity in vivo is more markedly pronounced than that of our estrogen receptor-positive TSC2-null cells when stimulated with estradiol in vitro, suggesting that estradiol may act elsewhere in vivo to promote LAM progression. Recent immunophenotyping of LAM-like TSC2-null uterine tumors revealed preferential increase in polymorphonuclear cell (PMNs) numbers of the tumor microenvironment; we also determined that PMNs are important regulators of tumor growth. Therefore, we hypothesize that, in addition to direct effects of estrogen on tumor cells, estrogen might also stimulate tumor growth by promoting PMN production in the bone marrow and actions in the tumor microenvironment. Here, we show that estrogen availability influences PMN mobilization in naïve and tumor-burdened mice. Using bone marrow cultures and CFC assay, we demonstrate that estradiol is a potent inducer of PMN production in chronic inflammatory conditions. Employing both pharmacologic agents and estrogen receptor (ER)-null bone marrow, we showed that ERα is necessary for promoting induction of PMN fate for myeloid progenitors. While we see that the migratory, invasive, and proliferative capacities of TSC2-null cell lines are not augmented when stimulated with E2 directly, experiments are underway to assess the extent to which estrogen promotes the pro-tumorigenic function of PMNs co-cultured with TSC2-null cell lines. Together these data provide insight into the robust effect of in vivo estrogen stimulation as estradiol may be a dual effector in LAM tumor progression and great target for anti-LAM therapeutic strategy.
Presentation: Saturday, June 11, 2022 1:00 p.m. - 1:05 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
PSAT018 Management of Pheochromocytoma in the Setting of a Patient with Multiple Vasculopathies
Authors: Khan Abdul , Lightell James , Majors Corey , Alls William 
Published: November 2022

Abstract

A 66-year-old male with history of Type 2 diabetes and adrenal incidentaloma presented to the hospital with significant left lower limb edema and was found to have severe peripheral vascular disease. CT surgery was consulted and performed an angiogram as well as an angioplasty; however, the patient had severe stenosis and stenting was not possible. Femoral popliteal bypass was planned. Due to the patient's acute kidney injury from renovacular hypertension, preoperative evaluation included a MRI abdomen w/wo contrast which showed a 1.4 cm right adrenal nodule with early contrast enhancement which appeared fairly avid and uniform. This nodule had been previously noted by CT scan three years prior. Previous outpatient labs showed elevated metanephrines of 543 pg/mL, which determined the adrenal nodule to be consistent with a pheochromocytoma. Subsequently, femoral popliteal bypass was postponed and the patient was started on an alpha blocker, doxazosin. Urology was consulted and right laproscopic adrenalectomy was planned. Preoperatively, patient developed chest pain due to ventricular tachycardia and NSTEMI was diagnosed by EKG. Patient then underwent a LHC which revealed severe left main 3 vessel coronary artery disease, postponing planned adrenalectomy. CABG was performed with pericardiectomy. After initial recovery, patient was discharged to in-patient rehabilitation, indefinitely delaying definitive pheochromocytoma therapy.

Reference
Jacques W. M. Lenders, Quan-Yang Duh, Graeme Eisenhofer, Anne-Paule Gimenez-Roqueplo, Stefan K. G. Grebe, Mohammad Hassan Murad, Mitsuhide Naruse, Karel Pacak, William F. Young, Jr, Pheochromocytoma and Paraganglioma: An Endocrine Society Clinical Practice Guideline, The Journal of Clinical Endocrinology & Metabolism, Volume 99, Issue 6, 1 June 2014, Pages 1915–1942, https://doi.org/10.1210/jc.2014-1498
Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.