bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PS19-08: Intratumoral heterogeneity of second-harmonic generation scattering from tumor collagen and its effects on metastatic risk prediction
Authors: Brown Edward , Desa Danielle , Wu Wencheng , Hill Robert , Martens John , Strawderman Robert , Turner Bradley 
Published: February 2021

Abstract
Second harmonic generation (SHG) is an intrinsic optical signal that can be generated from fibrillar collagen. The directionality of SHG emission is influenced by the diameter and spacing of collagen fibrils, and the disorder in their packing within collagen fibers. One measure of SHG directionality is the ratio of forward- to backward-scattered SHG, or “F/B”. F/B has been used to assess healthy vs diseased tissue in breast, ovarian, and lung cancer, and is an independent prognostic indicator of metastasis free survival time in ER+, lymph node-negative (N0), invasive ductal carcinoma (IDC). Here we assess the heterogeneity in F/B within tumor sections from ER+ N0 IDC, and its effect on the use of F/B for metastatic risk prediction. We find that F/B of tumor collagen varies between the tumor/host interface and the more cellular tumor bulk (p&lt;0.0001, Student’s t-test), and that F/B from the tumor/host interface, but not tumor bulk, is prognostic of metastasis free survival in 95 IDC ER+ N0 patients (p=0.0020 and 0.10, respectively, log rank test for trend). This result was repeated with two additional image analysis procedures to generate F/B with reduced user input and hence reduced possibility of bias. Using Random Survival Forests to generate a data-driven predictive model, we find that F/B from the tumor/host interface, but not bulk, as well as a 21-gene prognostic score inferred from Affymetrix data, both contribute to predicting metastasis-free survival in this cohort. Any tool to help predict metastasis and assist with treatment decisions is likely to be applied in combination with the now well-established genomic scores. To understand how F/B can support genomic methods for guiding treatment decisions we divided our patient samples into two cohorts based upon the value of their 21-gene score relative to the TAILORx cutoff of 26 (separating low-intermediate and high-risk groups). The F/B value from tumor-host interface identifies a subgroup of patients in the low-intermediate risk group with poor clinical outcome (p=0.045, log rank test for trend). Overall, this data reveals that intratumor heterogeneity can impact the ability of F/B to predict patient outcome, and that F/B specifically from the tumor-host interface may provide a tool to better identify patients in need of adjuvant treatment or enrollment in clinical trials.
Citation Format: Edward Brown, Danielle Desa, Wencheng Wu, Robert Hill, John Martens, Robert Strawderman, Bradley Turner. Intratumoral heterogeneity of second-harmonic generation scattering from tumor collagen and its effects on metastatic risk prediction [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS19-08.
Abstract PS19-14: Matrin3 inhibits breast cancer growth by suppressing microtubule nucleation protein MZT2B
Authors: Subbarayalu Panneerdoss , Rajamanickam Subapriya , Viswanadhapalli Suryavathi , Li Fuyang , Eedunuri Vijay , Yadav Pooja , Reddy Esha , Timilsina Santosh , Nirzhor Saif SR , Onyeagucha Benjamin C , Wang Li-Ju , Chiu Yu-Chiao , Mohammad Tabrez , Abdelfattah Nourhan , Dybdal-Hargreaves Nicholas , Chen Yidong , Vadlamudi Ratna , Rao Manjeet 
Published: February 2021

Abstract
Despite improvement in overall survival, many patients with breast cancers still succumb to this disease. Identification of new biomarkers and safe therapeutic targets are urgently needed to improve the overall clinical outcome of breast cancer patients. Our studies discovered a RNA binding protein, MATRIN3 (MATR3), as a novel tumor suppressor. MATR3 is expressed at a significantly reduced levels in breast tumors. MATR3 inhibited short and long-term viability as well as migration and invasion of breast cancer cells. Further, MATR3 overexpression suppressed tumor growth, while its depletion induced tumor growth in orthotopic mouse tumor models. RNA seq and RNA immunoprecipitation analyses revealed that MATR3 binds and directly regulates the expression of several microtubule-associated proteins. Mechanistic studies identified MZT2B, a mitotic spindle organizing protein as a down stream effector of MATR3. MZT2B knockdown or knockout using CRISPR-CAS9 resulted in significantly decreased short and long term viability as well as reduced migration and invasion of breast cancer cells. Notably, MZT2B overexpression rescued the inhibitory effect of MATR3 overexpression on breast cancer growth. Furthermore, MATR3 overexpression downregulated expression of key microtubule nucleation protein complex including γ-tubulin and γ-tubulin ring complex protein (TUBGCP). Our data suggest that MATR3 inhibits breast cancer growth and progression by inhibiting MZT2B and consequently microtubule nucleation in breast cancers.
Citation Format: Panneerdoss Subbarayalu, Subapriya Rajamanickam, Suryavathi Viswanadhapalli, Fuyang Li, Vijay Eedunuri, Pooja Yadav, Esha Reddy, Santosh Timilsina, Saif SR Nirzhor, Benjamin C Onyeagucha, Li-Ju Wang, Yu-Chiao Chiu, Tabrez Mohammad, Nourhan Abdelfattah, Nicholas Dybdal-Hargreaves, Yidong Chen, Ratna Vadlamudi, Manjeet Rao. Matrin3 inhibits breast cancer growth by suppressing microtubule nucleation protein MZT2B [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS19-14.
Abstract PS19-15: N-RAS as a marker for DCIS progression
Authors: Chang Eric C , Zheng Zeyi , Elsarraj Hanan , Hong Yan , Shen Yichao Shen , Lo Flora , Feng Long , Zhang Xian H.-F. , Behbod Fariba 
Published: February 2021

Abstract
Background: Ductal carcinoma in situ (DCIS) is a key premalignant stage. Approximately 50% of the DCIS cases will advance to invasive ductal carcinoma (IDC); however, they are usually universally treated leading to overtreatment. While earlier premalignant breast lesions, such as atypical ductal hyperplasia, are nearly all luminal and positive for estrogen receptor α (ER+), up to 8% DCIS are basal-like, which is more aggressive. We have previously shown that N-Ras, which is highly expressed selectively in the basal-like subtype, can promote the growth and transforming activity of basal-like breast cancer (PMID 26166574). In this study we investigate whether NRAS expression at DCIS can promote basal-like properties and the progression to invasiveness.
Methods: NRAS mRNA levels in normal, DCIS, and IDC patient-derived microarray databases and tissue microarrays (TMAs) were compared using student t-test. Correlation between NRAS mRNA levels and basal-like properties was assessed by Pearson Correlation. ER protein levels were assessed by IHC. NRAS was expressed in a luminal DCIS cell line model SUM225PE cells and the resulting cells were injected intraductally into mice to assess expression of basal-like markers and invasiveness in vivo. Conversely, NRAS expression was silenced in a DCIS-like basal-like cell line SUM102 and increased expression of luminal markers was assessed by RNA-seq and western blot.
Results: In microarray databases, DCIS samples with higher NRAS mRNA levels are enriched with basal-like gene expression signature; furthermore, NRAS mRNA levels appear to increase progressively from normal to DICS and from DCIS to IDC. A similar correlation between high NRAS levels and invasiveness and high Ki67 levels in TMAs was observed by RNA FISH. High levels of NRAS mRNAs also correlated with low ER levels.
Conclusions: How to identify the subset of DCIS cases that will become invasive is critical for addressing the current problem of overtreatment. Our data support the hypothesis that high N-RAS levels in DCIS mark invasiveness, by presumably inducing basal-like more aggressive tumor activities. On-going studies will further delineate whether N-Ras is also responsible for driving DCIS to the invasive state.
Citation Format: Eric C Chang, Zeyi Zheng, Hanan Elsarraj, Yan Hong, Yichao Shen Shen, Flora Lo, Long Feng, Xian H.-F. Zhang, Fariba Behbod. N-RAS as a marker for DCIS progression [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS19-15.
Abstract PS19-17: The role of myoglobin in breast cancer
Authors: Aboouf Mostafa A. , Armbruster Julia , Guscetti Franco , Thiersch Markus , Gassmann Max , Gorr Thomas A. 
Published: February 2021

Abstract
Breast cancer today is typically seen as malignancy with longer survival due to early-detection diagnostics, yet the cancer remains by far the most common tumor type in adult females. Recently, our group co-discovered myoglobin (MB) to be expressed in luminal cells of healthy and cancerous breast epithelia of human and mice. In human patients, MB positivity emerged as hallmark of the luminal subtype and was directly correlated with estrogen receptor alpha positivity and hence a significantly better prognosis. Cancerous cells’ MB also appears to interact with the known tumor suppressor p53. However, if and how myoglobin itself restricts mammary tumorigenesis is completely unclear. To understand how MB exerts its alleged tumor-suppressive effects and if it impacts response of mammary tumors to chemo- and/or radiotherapy, we examine the molecular role of MB in breast tumor formation and progression through a) in vitro studies (MCF7 breast cancer BrCa cell clones; wildtype (wt) controls versus CRISPR/Cas9-engineered clones of a MB and/or p53 knockout (MBko/p53ko), b) in vivo mouse models to obtain spontaneously forming breast tumors, with or without MB, in a p53 deficient background. Comparing MCF7 BrCa MBko and p53ko clones vs. their corresponding wildtype counterpart supports our hypothesis of a feed forward loop between MB and p53 proteins, besides interfering with estrogen receptor expression. In addition to that, loss of MB was noticed to exert p53-independent upregulation on cell cyclins with more S phase cell population. That was reflected by a significant increase in survival of the MBko cells, in presence or absence of p53. Hypoxic MBko cells exhibited a partial epithelial to mesenchymal transition and hence a more migratory phenotype, relative to MBwt controls. Additionally, MB seems to stimulate apoptosis of the normoxic cancer cells. On the other hand, murine tumors were found to phenocopy human BrCa in the extent of their MB expression. Interestingly, MB-devoid tumors showed a significantly higher proliferation index and fat accumulation. Further studies will look into the clinical significance of that. In conclusion, MB seems to occupy unknown roles in cancer cells beyond or different from its classical O2 storage/transport functions. Unraveling these novel roles in governing tumor development and virulence will hopefully provide innovative strategies for future breast cancer interventions.
Citation Format: Mostafa A. Aboouf, Julia Armbruster, Franco Guscetti, Markus Thiersch, Max Gassmann, Thomas A. Gorr. The role of myoglobin in breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS19-17.
Abstract PS19-21: Tak1 signaling regulates p53 through a mechanism involving ribosomal stress
Authors: Bakin Andrei , Zonneville Justin 
Published: February 2021

Abstract
Triple-negative breast cancer (TNBC) is among the most aggressive forms of breast cancer with limited therapeutic options. TAK1 is implicated in aggressive behavior of TNBC, while means are not fully understood. Here, we report that pharmacological blockade of TAK1 signaling hampered ribosome biogenesis (RBG) by reducing expression of RBG regulators such as RRS1, while not changing expression of ribosomal core proteins. Importantly, TAK1 blockade upregulated expression of p53 target genes in cell lines carrying wild type (wt) TP53 but not in p53-mutant cells. By examining involvement of the ribosomal stress response, we found that p53 activation by blockade of TAK1 was prevented by depletion of ribosomal protein RPL11. Further, siRNA-mediated depletion of TAK1 or RELA resulted in activation of p53 signaling and this response was dependent on RPL11. Knockdown of RRS1 disrupted nucleolar organization and resulted in activation of p53. Genomic TCGA data showed that TNBCs express high levels of ribosome biogenesis regulators, and elevated RRS1 levels correlate with unfavorable prognosis. Cytotoxicity data showed that TNBC cell lines are more sensitive to TAK1 inhibitor compared to luminal and HER2+ cell lines. Together, the data indicate that TAK1 regulates p53 activation by controlling ribosome biogenesis factors, and the TAK1-ribosome axis is a potential therapeutic target in TNBC.
Citation Format: Andrei Bakin, Justin Zonneville. Tak1 signaling regulates p53 through a mechanism involving ribosomal stress [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS19-21.
Abstract PS19-28: Thymoquinone and tamoxifen co-treatment synergistically inhibit proliferation, invasion and induce apoptosis in human breast cancer cell lines in vitro and in vivo
Authors: Yahiya Islam , Helmy Heba , Sultan Ahmed 
Published: February 2021

Abstract
Epidemiological studies and experimental analysis indicate that dietary factors influence thedevelopment of breast cancer, suggesting the role of natural products as modifying factors againstbreast cancer. Thymoquinone (TQ) (a dietary phytochemical compound) the main active ingredientof the volatile oil of black seed (Nigella sativa) has been used to be safe when administered to awide variety of normal cells. In addition, Tamoxifen (TAM), a nonsteroidal triphenylethylene derivateand selective ER modulator, has been used as a single agent in the treatment of ER positive breastcancer.In the present study, we report the possible chemo-sensitizing effect of TQ as a promisingconventional chemotherapeutic agent, using a panel of human breast cancer cell lines, MCF-7, ZR-75-1, T-47D and BT-20 respectively in vitro and in vivo.Our data revealed that TQ, TAM or combined treatments significantly inhibited cell viability of MCF-7, T-47D, ZR-75-1 but slightly of BT-20 cell lines consistently with down-regulation of signaltransducer and activator of transcription 3 (STAT 3), mTOR, cyclin D1, oncogenic β-catenin,signaling a specific transcription factor and PPAR-gamma in a dose dependent manner. Mostimportantly, combined treatment enhanced inhibition of cell viability, DNA fragmentation andapoptosis induction through Caspase-3 activation and Bcl-2 down regulation in all tested cell linesbut this effect was limited in BT-20 cells compared to controls. Moreover, our data was supported bymicroscopic examination using electron scanning microscopy that revealed many apoptoticalterations after combined treatment compared to each TQ or TAM. Furthermore, confocalfluorescence microscopy examination revealed that only combined treatment showed a significantinhibition of filopodia formation as a sign of invasion inhibition in both BT-20 and MCF-7 humanbreast cancer cell lines. In vivo, tumor xenotransplants of human ZR-75-1 cells revealed that onlycombined treatment showed a significant regression in tumor size by 53% after 72h and enhancedE-cadherin expression as analyzed by immunohistochemistry and confocal fluorescencemicroscopy.Taken together, our findings provide strong in vitro and in vivo molecular evidences in support ofour hypothesis that Thymoquinone synchronized as chemo-preventive agent with Tamoxifen to inhibithuman breast cancer cell lines proliferation, invasion and induce apoptosis that might have a potentialimplication in breast cancer prevention and treatment.
Citation Format: Islam Yahiya, Heba Helmy, Ahmed Sultan. Thymoquinone and tamoxifen co-treatment synergistically inhibit proliferation, invasion and induce apoptosis in human breast cancer cell lines in vitro and in vivo [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS19-28.
Abstract PS2-39: A peninsular experience - developing a non-biopsy protocol for the female cohort 25-29 years with clinically typical fibroadenoma conforming to maxwell criteria on ultrasound
Authors: Arif Tahera , Absar Mohammed Shameem , Vinayagam Raman 
Published: February 2021

Abstract
Abstract.Abstract1:
IntroAim: The aim of this study was to introduce a non -biopsy protocol in our department for benign breast lump referrals confirmed as typical U2/3 fibroadenoma on imaging. The cohort of women between 25-29 years of age with sonographic features (Maxwell non-biopsy criteria) U2/3 typical of fibroadenoma does not miss malignancy. Current UK guidance is not to biopsy sonographically typical fibroadenomas in women under 25 years. We have studied our population extending the radiological Maxwell criteria reflecting histologically benign outcomes even in this group of 25-29 years.MethodsMethods: Retrospectively data was collected of all women between 25-29 years of age undergoing core biopsy for ultrasound confirmed both simple and complex fibroadenomas at Clatterbridge General Hospital between 2014 and 2019 over a period of five years. The number of cancers picked up was compared with the number of referrals and the discordance between radiological diagnosis of fibroadenoma and histopathological confirmation of malignancy was recorded.ResultsResults: We saw increment in referrals in this group of young women from n=260 to n=386 over the five year study period. A total of 1707 referrals were made across five years. n=175 image guided core biopsies were carried out for U2,U3,U4 lesions appearing as fibroadenoma on ultrasound. Out of these (n=175), all lesions coded U2/3 (n=165) based on Maxwell criteria on ultrasound were negative for cancer. U4 lesions on ultrasound were confirmed as cancers mimicking fibroadenoma(n=10).ConclusionConclusion: This retrospective audit of 1707 patients provides sound evidence for safe non-biopsy of typical fibroadenomas in women 25-29 years when clinical and sonographic features meet strict criteria. We started using the non-biopsy protocol using Maxwell criteria for U2/3 lesions. We discharged women in this group if they met all the protocol criteria, i.e., their lesion does not appear suspicious clinically, has all the ultrasound appearances typical of a fibroadenoma U2/3, and they do not have any compounding circumstances (e.g., family history, genetic predisposition). As routine, we advise all women who are discharged without follow-up to examine their breasts regularly and return if they detect any changes including increase in lesion size. We need data to be audited prospectively and provide level 1 evidence to the same effect.
Citation Format: Tahera Arif, Mohammed Shameem Absar, Raman Vinayagam. A peninsular experience - developing a non-biopsy protocol for the female cohort 25-29 years with clinically typical fibroadenoma conforming to maxwell criteria on ultrasound [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS2-39.
Abstract PS3-20: Rapid beside diagnosis of breast core needle biopsies using stimulated raman histology
Authors: Orringer Daniel Avram , Chen Thomas , Pastore Steve , Darvishian Farbod , Toth Hildegard , Schnabel Freya 
Published: February 2021

Abstract
Image-guided core needle biopsy plays a central role in the diagnosis and management of a wide range of breast lesions. After collection, tissue cylinders are transported from a biopsy suite to a pathology laboratory for analysis. The existing workflow for microscopic diagnosis of tissue specimens precludes the option of using histologic data to inform clinical decision-making at the time of biopsy. Here, we introduce stimulated Raman histology (SRH), a rapid label-free optical imaging method that enables microscopic imaging of unprocessed breast biopsy specimens in the biopsy suite within minutes of sample collection. SRH has been thoroughly validated for use in the detection and diagnosis of brain tumors but its use has not been validated in breast lesions. In our study, we collected core needle biopsy specimens and allocated a 2mm portion of the tissue sample for SRH imaging. Each specimen was imaged with SRH and subsequently fixed in formalin, embedded, stained and sectioned in a conventional manner. A board-certified breast pathologist first analyzed the diagnostic features of the imaged specimens with SRH and then with conventional H&E-stained sections. In a pilot series of six patients, we found that SRH could differentiate between lesions that can mimic cancer such as a radial scar from neoplastic ones like invasive ductal carcinoma. SRH also demonstrated histologic differences between a benign tumor like a fibroadenoma and a malignant tumor like an invasive ductal carcinoma. We also observed diagnostic differences amongst benign processes such as radial scar and pseudoangiomatous stromal hyperplasia. Importantly, we showed that SRH is non-consumptive and the imaged tissue can be used for downstream histologic and immunohistochemical analysis. Our data provide proof of concept that SRH can reveal the diagnostic features of tissue collected in breast core needle biopsies, supporting further validation of this technology. Ultimately, we envision the use of SRH to create new, efficient workflows for managing patients with breast lesions, especially those in which fine needle aspiration is of limited value, and where rapid diagnosis of tissue biopsies could streamline care and increase patient satisfaction.
Citation Format: Daniel Avram Orringer, Thomas Chen, Steve Pastore, Farbod Darvishian, Hildegard Toth, Freya Schnabel. Rapid beside diagnosis of breast core needle biopsies using stimulated raman histology [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS3-20.