tbuckley/cabot-search huggingface dataset:
Abstract PO3-29-03: An Emerging Class of ER mutations Enhances ER Dimerization and Promotes ER Activity
Authors: Seema Irani, Wuwei Tan, Qing Li, Weiyi Toy, Catherine Jones, Mayur Gadiya, Antonio Marra, John Katzenellenbogen, Kathryn Carlson, Benita S. Katzenellenbogen, Yang Shen, Sarat Chandarlapaty
Journal: Cancer Research (2024)

Abstract Physiological activation of estrogen receptor alpha (ERα) requires the binding of estradiol (E2) to the ligand binding domain (LBD) of the receptor. This interaction triggers a repositioning of helix 12 (H12), facilitating the recruitment of coactivator proteins to the unoccupied coactivator binding groove. However, in the context of breast cancer, point mutations of ERα at H12 lead to its repositioning and self-activation in the absence of E2. Through MSK clinical sequencing breast cancer cohort (MSK-IMPACT), we assayed 8302 samples of ER+ breast cancer patients and identified 649 mutations within the LBD of ERα. 471 of these mutations (73%) were located at H11-H12 loops (D538, Y537, L536), while the remaining 27% were located near the dimer interface of ERα (V422, G442, F461, S463P, L469). Through in vitro biochemical and cell assays, we identified that these mutations promote dimer formation and hormone-independent transcriptional activity. Tumors expressing these mutations exhibited significantly accelerated growth compared to their wild-type controls. Unlike Y537S, cells harboring mutations at the dimer interface maintain their sensitivity to Selective Estrogen Receptor Degraders (SERDs), including Fulvestrant, recently FDA-approved Elacestrant, and Camizestrant, as well as Selective Estrogen Receptor Modulators (SERMs) including Tamoxifen and Raloxifene. By utilizing machine learning and computational structural analyses, we uncovered that these mutants, unlike Y537 repositions H12, act distinctly through conformational change across the ERα dimer interface. Further cell assays proved that the dimerization leads to increased stability of the receptor and facilitates its nuclear localization, which is required for ERα activation. Collectively, our finding unveiled a new class of ER mutations that enforce receptor dimerization and activation of the ER signaling pathway. The discovery opens up a new therapeutic interventional possibility, suggesting that targeting dimerization could emerge as a new strategy to combat these malignancies. Citation Format: Seema Irani, Wuwei Tan, Qing Li, Weiyi Toy, Catherine Jones, Mayur Gadiya, Antonio Marra, John Katzenellenbogen, Kathryn Carlson, Benita S. Katzenellenbogen, Yang Shen, Sarat Chandarlapaty. An Emerging Class of ER mutations Enhances ER Dimerization and Promotes ER Activity [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-29-03.
Abstract PO3-24-12: CRIPTO-regulated extracellular vesicles mediate heterotypic cellular crosstalk in triple negative breast cancers
Authors: David Freeman, Benjamin Spike, Brooke Gates
Journal: Cancer Research (2024)

Abstract Tumor progression involves the dynamic interaction between various cell types within the tumor microenvironment. Fibroblasts, which normally participate in wound healing, exhibit reciprocal communication with breast cancer cells that contributes to tumor cell plasticity and heterogeneity. Gaining insights into the molecular mechanisms underlying cell-to-cell communication, which drive cellular plasticity and play a pivotal role in breast cancer progression and metastasis, has the potential to unlock novel avenues for targeted therapeutic interventions. The small GPI-adaptor protein CRIPTO is a key player in this context. CRIPTO orchestrates the activity of TGF-β and growth factor-like signaling pathways that activate c-Src/MEK/AKT. CRIPTO is expressed during mammary development, wound healing, and breast cancer but is largely undetectable in homeostatic tissue, making it a promising therapeutic target. Our previous studies have demonstrated that the activity of CRIPTO is contingent upon cellular stress, with pronounced influence within pro-fibrotic, hypoxic domains of tumors. Importantly, we have shown that inhibition of CRIPTO using the soluble recombinant protein antagonist A4Fc effectively impedes the progression of triple negative breast cancer (TNBC) in murine xenograft models. Building upon these findings, we have been dissecting CRIPTO‘s role in coordinating fibroblast activation and cell-state reprogramming in TNBC. Notably, we have found that inhibition of CRIPTO with A4Fc suppresses cancer associated fibroblast (CAF) activation and collagen remodeling in vivo. And, by modeling tumor cell:fibroblast crosstalk using in vitro organoid co-cultures, we have demonstrated CRIPTO expression in tumor cells is necessary for extracellular vesicle (EV) uptake by fibroblasts, their SMAD pathway activation and their priming for reciprocal signaling back to tumor cells to for transcriptional reprogramming and cellular invasion. The significance of these findings lies in their potential to pave the way for the development of new therapies specifically targeting crucial tumor cell:fibroblast crosstalk mechanisms at primary and metastatic sites. Plasticity targeting therapies are urgently needed in the treatment of TNBC and other malignancies, and hold great promise for improving patient outcomes. Citation Format: David Freeman, Benjamin Spike, Brooke Gates. CRIPTO-regulated extracellular vesicles mediate heterotypic cellular crosstalk in triple negative breast cancers [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 PO3-24-12.
Abstract PO2-27-02: Re-sensitizing the Refractory Breast Cancer Bone Metastasis to Endocrine Therapies
Authors: Anindita Das, Cheyenne Ernst
Journal: Cancer Research (2024)

Abstract Approximately 90% of Breast Cancer (BrCa) related deaths are caused by metastasis and bone is the first and most frequent site of breast cancer metastatic expansion, which can lead to severe pain, immobility, fractures, and nerve damage, as well as the development of metastases in other organs, hence; a poor quality of life in patients. Currently, treatment options for these bone metastases (BoM) are limited because most patients with BoM shows reduced ER dependency which leads to resistance to standard endocrine or hormonal therapies for estrogen receptor-positive (ER+) BrCa. The long-term goal of the proposed research is to develop a strategy where metastatic cancer cells in bone can be dependent on ER signaling again thereby restoring their sensitivity to endocrine therapies. We observed a transient loss of ER expression in concert with enhanced activity of the transcriptional coactivators YAP/TAZ - the downstream effectors of the Hippo pathway (responsible for regulating cell proliferation and death) during bone colonization by BrCa cells. We hypothesize that the interaction between cancer cells and osteoblasts in the bone microenvironment leads to the activation of calcium signaling in cancer cells, resulting in the de-phosphorylation and nuclear localization of YAP/TAZ which subsequently suppresses the transcription of the estrogen receptor gene (ESR). Our research strategy is as presented below. First, we will employ a combination of 2D/3D co-culture models of BoM along with a mechanical loading system and determine the molecular mechanism driving the dynamical activation of YAP/TAZ in BrCa BoM. Using a unique ex vivo BM model called Bone In Culture Array (BICA) which replicates the in-vivo conditions, we will determine if verteporfin, a YAP/TAZ antagonist, can synergize and possibly enhance the effects of Fulvestrant, an ER antagonist in current use for certain types of BrCa in preventing BoM outgrowths and treating established BoM in mice. This research could ultimately lead to a favorable combination strategy to treat endocrine-resistant BoM in BrCa patients and prolong their survival. Citation Format: Anindita Das, Cheyenne Ernst. Re-sensitizing the Refractory Breast Cancer Bone Metastasis to Endocrine Therapies [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 PO2-27-02.
Abstract PO2-26-05: Disparities at the Convergence of Race and Ethnicity: Examining Trends and Outcomes in Young Women Diagnosed with Breast Cancer
Authors: Ragisha Gopalakrishnan, Esha Gandhi, Maria Fernandez
Journal: Cancer Research (2024)

Abstract Purpose: In breast cancer, research has shown that race/ethnicity can be associated with disease predisposition, access to care, and outcomes. There are numerous studies that combine Hispanic and Haitian women of all races into a single group may overlook opportunities to identify important characteristics within this heterogeneous group that could more accurately predict outcomes and reveal opportunities to improve care. While these groups have been studied, there is limited data about the impact race and ethnicity has on young adult populations with breast cancer. In this study, we sought to compare tumor subtype, stage at diagnosis, time to surgery (TTS), and overall survival (OS) among Hispanic and Haitian patients to patients of non-Hispanic descent. Methods: Women 18 years of age or older who had been diagnosed with stage 0-IV breast cancer and who had undergone lumpectomy or mastectomy were identified in the National Cancer Database (2015-2021). Tumor subtype and stage at diagnosis were compared by race/ethnicity. Multivariable linear regression and Cox proportional hazards modeling were used to estimate associations between race/ethnicity and adjusted TTS and OS, respectively. Results: A total of 48,150 patients were included in this study. Age ranged from 18-40. (American Indian [AI]: 79 [0.2%]; Haitian: 15,011 [31.2%]; White: 20,109 [85.48%]; Hispanic: 13,030 [27%]. Hispanic women had higher rates of triple-negative disease (23.9%) than did Haitian women (11.5%) and white women (10.9%; P &amp;lt; .001). Hispanic women had higher rates of node-positive disease (26.2%) in comparison to Haitian women (17%) and Non-Haitian/Hispanic women (10% P &amp;lt; .001). Hispanic women had worse PFS when diagnosed at Stage II and III (37 and 39 months, respectively) than Haitian women (57 and 59 months, respectively) and Non-Haitian/Hispanic women (82 and 87 months). Hispanic women had worse OS when diagnosed at Stage II and III (45 and 49 months) than Black women (70 and 75 months) and non- women (95 and 99 months). Conclusion: Hispanic women had worse PFS versus non-Hispanic and Haitian women as well as present with high-risk characteristics and nodal disease at the time of presentation. This suggests that racial differences in tumor subtype and nodal stage among Hispanic women highlight the importance of developing additional studies which can investigate the disparity in patient outcomes with young Hispanic women in breast cancer research. Citation Format: Ragisha Gopalakrishnan, Esha Gandhi, Maria Fernandez. Disparities at the Convergence of Race and Ethnicity: Examining Trends and Outcomes in Young Women Diagnosed with 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 PO2-26-05.
Abstract PO3-07-12: Effect of neoadjuvant chemotherapy on peritumoral edema in early stage breast cancer and its prognostic value
Authors: Hideo Shigematsu, Mutsumi Fujimoto, Yoshie Kobayashi, Tomoyuki Yoshiyama, Noriaki Matsuura, Daisuke Komoto, Kazuya Kuraoka
Journal: Cancer Research (2024)

Abstract Objectives: We aimed to evaluate the effect of neoadjuvant chemotherapy (NAC) on peritumoral edema (PE) and its prognostic value in operable breast cancer. Materials &amp; Methods: This retrospective study included 128 cT1-4N0-3M0 breast cancer patients who underwent contrast-enhanced magnetic resonance imaging (MRI) of the breast before and after anthracycline- and/or taxane-based NAC, followed by curative surgery at our hospital, between 2006 and 2016. T2-weighted MRI revealed PE, and PE before NAC (pre-PE) and PE after NAC (residual PE) were evaluated. The correlation between the presence or absence of PE and relapse-free survival was evaluated using a log-rank test and multivariable Cox regression analysis. The risk of recurrence was stratified according to the residual cancer burden (RCB). Results: Pre-PE was observed in 64 out of 128 patients (50%). Among 64 patients with pre-PE-positive breast cancer, residual PE was observed in 21 (32.8%). In the log-rank test, breast cancer with residual PE had a poorer prognosis than breast cancer with PE that had disappeared (p &amp;lt; 0.0001). In the multivariable Cox regression analysis, residual PE was a significant factor of poor prognosis (RR, 20.5; 95% confidence interval, 5.3–108.2; p &amp;lt; 0.0001). Regarding RCB stratification, compared to patients with breast cancer with disappeared PE, those with breast cancer with residual PE exhibited significantly poor prognosis in class II and class III (p = 0.006, 0.02). Conclusion: In breast cancer with PE, residual PE after NAC is a significant factor related to poor prognosis. Effect of neoadjuvant chemotherapy on peritumoral edema in patients with breast cancer and its clinical significance XX XX Citation Format: Hideo Shigematsu, Mutsumi Fujimoto, Yoshie Kobayashi, Tomoyuki Yoshiyama, Noriaki Matsuura, Daisuke Komoto, Kazuya Kuraoka. Effect of neoadjuvant chemotherapy on peritumoral edema in early stage breast cancer and its prognostic value [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 PO3-07-12.
Abstract PO3-29-05: Clinical risk score to predict overall survival and breast cancer recurrence in phase 3 TAILORx trial and the Surveillance, Epidemiology, and End Results (SEER) Database populations
Authors: Sherry Yang, John Yu, Ninet Sinaii
Journal: Cancer Research (2024)

Abstract Background: Overall survival (OS) is the gold standard and most relevant endpoint in oncology research and patient care. It underscores a need to develop methods to estimate the likelihood of mortality in breast cancer. Methods: We evaluated molecular and clinical measures that predicted mortality risk using multiple logistic regression and developed a clinical risk score (CS) in 8,905 patients from the phase 3 TAILORx trial. Association of CS with mortality in patients at low, intermediate, and high risks was analyzed by Kaplan-Meier and multivariable Cox proportional-hazards regression analyses. The score was validated in an independent population of 148,301 patients with node-negative, hormone-receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer in the SEER database. Likelihood ratio (LR) test and c-index were used to compare prognostic information provided by CS and a 21-gene recurrence score (RS) to OS, invasive disease-free survival (DFS), recurrence-free interval (RFI), and distant recurrence-free interval (dRFI). Results: The 10-year mortality rates in low-risk, intermediate risk, and high-risk groups were 3.9% (95% CI 3.1 to 4.8), 37.2% (95% CI 23.4 to 51.1), and 75.8% (95% CI 54.1 to 97.4), respectively (P&amp;lt; 0.0001). Compared with low-risk score, intermediate (adjusted HR 45.5, 95% CI 32.2 to 64.9) and high-risk scores (HR 2026, 95% CI 1194 to 3483) were associated with risk of mortality, independent of demographics, tumor grade, RS, tumor size, PR, and treatment factors. The algorithm also predicted DFS, dRFI, and RFI outcomes (P&amp;lt; 0.0001 each), outperforming RS by both LR test and c-index estimate. Its validity was corroborated in the SEER population (intermediate risk: HR 9.3, 95% CI 6.7 to 13.3 and high-risk: HR 125.9, 95% CI 85.2 to 189.6). Conclusions: Clinical risk score robustly predicts risk of mortality in early-stage breast cancer populations. It provides more prognostic information than RS to survival and breast cancer recurrences. Citation Format: Sherry Yang, John Yu, Ninet Sinaii. Clinical risk score to predict overall survival and breast cancer recurrence in phase 3 TAILORx trial and the Surveillance, Epidemiology, and End Results (SEER) Database populations [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-29-05.
Abstract PO2-26-06: Prognostic factors pregnancy associated breast cancer: one year versus two years
Authors: Maxim Izquierdo, Sonia Baulies, Carmen Ara, Maria Garcia, Fransec Fargas, Rafael Fabregas, Fransec Tresserra, Pere Barri S
Journal: Cancer Research (2024)

Abstract Aims: The trend of delayed delivery, the number of women with breast cancer during a pregnancy or in the years after pregnancy is expected to increase Pregnancy breast cancer confers a worse prognostic. Study if the interval pregnancy breast cancer more one year to two years influences the prognostic factors like pregnancy breast cancer one year after Methods: Study 1186 patients with breast cancer and prognostic factors. Analyze delivery before breast cancer, and the interval of last childbirth, one year, more one year to two years and more two years, with prognostic factors (nodes, estrogen receptor, progesterone receptor, HER2 receptor and Ki 67) Results: Breast cancer pregnancy one year after were in 37 patients, more one year to two years in 25 patients and more two years in 491 patients. Positive nodes one year after were in 21 patients, more one year to two year were in seven patients (p &amp;lt; 0'05), and more two years in 155 patients (p=ns). There are not differences (p=ns) in estrogen receptor, progesterone receptor and Ki67, one year versus more one year to two years and more to two years. HER2 and histologic grade there are not differences (p=ns) in one year after versus more one year to two years, but there are differences (p &amp;lt; 0’05) versus more two years Conclusion: Interval last childbirth breast cancer more than one year to two years influences prognostic factors for later breast cancer, and not have differences with prognostic factors than pregnancy one year after Citation Format: Maxim Izquierdo, Sonia Baulies, Carmen Ara, Maria Garcia, Fransec Fargas, Rafael Fabregas, Fransec Tresserra, Pere Barri S. Prognostic factors pregnancy associated breast cancer: one year versus two years [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 PO2-26-06.
Abstract PO2-27-04: Unravelling the role of FGFR1 in innate immune sensing and endocrine resistance in breast cancer
Authors: Sushil Dhakal, Torbjørn Amundsen Lien, Jens Henrik Norum, Helga Bergholtz, Helene Midtun Flatekvål, Therese Sørlie
Journal: Cancer Research (2024)

Abstract Fibroblast Growth Factor Receptor 1 (FGFR1) has emerged as a critical player in various cancer types, including breast cancer. FGFR1 alterations, including gene amplification, overexpression, and activating mutations, have been identified in subsets of breast cancers, contributing to aberrant signaling pathways that promote tumor growth, angiogenesis, and metastasis. Our current research endeavors are directed towards unravelling the intricate mechanistic underpinnings of FGFR1's dual impact on breast tumor progression, specifically its contribution to endocrine resistance and its regulatory role in innate immune sensing and subsequent induction of Type 1 interferons (IFNs) Our investigative efforts have previously established a direct association between FGFR1 and endocrine resistance in hormone receptor positive T47D breast cancer cells. Moreover, a remarkable and distinct inverse correlation linking FGFR1 expression to the Type 1 IFN response was observed. We noticed that in vitro stimulation of T47D cells with Type 1 interferons induces the expression of FGFR1 and ESR1, thereby suppressing the interferon-stimulated genes. Interestingly, we observed that the FGFR1-mediated suppression of the Type 1 interferon response is associated with intracellular nucleic acid sensors, specifically toll-like receptors TLR7 and TLR9. Furthermore, we found that the inhibition of FGFR kinase enhances the expression of IFN-alpha, IFN-beta, TLR7, and TLR9 in T47D cells when stimulated with the TLR7 agonist loxoribine. These results strongly suggest that FGFR1 functions as an innate checkpoint and may be exploited by tumor cells to dampen Type 1 interferon responses, thereby inhibiting antitumor immunity in hormone receptor-positive breast cancer. Citation Format: Sushil Dhakal, Torbjørn Amundsen Lien, Jens Henrik Norum, Helga Bergholtz, Helene Midtun Flatekvål, Therese Sørlie. Unravelling the role of FGFR1 in innate immune sensing and endocrine resistance in breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-27-04.
Abstract PO2-27-08: Discovery of glucocorticoid receptor-induced EMT and integrin gene expression and increased cell motility in invasive lobular breast cancer
Authors: Baylee Porter, Candace Frerich, Muriel Laine, Sunati Sahoo, Geoffrey Greene, Jeon Lee, Lynda Bennett, Suzanne Conzen
Journal: Cancer Research (2024)

Abstract Estrogen receptor (ER)-positive, invasive lobular carcinoma (ILC) is the second most common histological subtype of breast cancer. Although the five-year stage-matched survival is improved compared to infiltrating ductal carcinoma (IDC), ILC late metastatic recurrences ( &amp;gt;5 years) are more frequent. Understanding the molecular mechanisms of lobular breast cancer’s significantly dormant yet ultimately metastatic phenotype is important to improve clinical outcomes. Our laboratory had previously shown that GR activation in ER+ IDC was associated with decreased cell proliferation, but little is known about GR activity in ER+ ILC. By examining gene expression following GR activation in metastases-derived ER+/GR+ human ILC cell lines, we recently uncovered that GR-activation increases EMT and integrin pathways. Here we show for the first time that in addition to activation of these gene expression pathways, GR activation increases ILC cellular migration in microchannels coated with collagen and fibronectin, consistent with a potential for GR activation to increase ILC metastases. We examined GR expression and activation in SUM44 GR+/GR-, and BCK4 GR+/GR- and MM134 GR+ cell lines and will present data comparing gene GR- mediated expression in the presence of cortisol and clinically relevant GR modulation. Ongoing investigations also include in vivo MIND modeling with GR modulation. Citation Format: Baylee Porter, Candace Frerich, Muriel Laine, Sunati Sahoo, Geoffrey Greene, Jeon Lee, Lynda Bennett, Suzanne Conzen. Discovery of glucocorticoid receptor-induced EMT and integrin gene expression and increased cell motility in invasive lobular 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 PO2-27-08.