bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P2-01-05: Targeting of casein kinase 1δ inhibits triple negative breast cancer metastasis
Authors: Bayle S , Lafitte M , Quereda V , Roush WR , Duckett DR
Published: May 2019

Metastasis is responsible for most breast cancer mortalities and 30% of the patients with breast cancer will develop metastases. Despite the establishment of efficient targeted therapies for breast cancer, there is no cure for metastatic disease. Our research team have developed a potent, highly selective, small molecule inhibitor of casein kinase-1 delta (CK1δ), a serine/threonine kinase. We have demonstrated that our lead molecule (SR-3029) provokes tumor specific cell death and tumor regression in pre-clinical orthotopic xenograft models of triple negative breast cancer (TNBC) including, basal-like patient derived (PDX) breast cancer models. Herein, we demonstrate that targeting CK1δ inhibits tumor cell invasion in cell based studies and markedly reduces both the number and size of metastasis lesions spreading from the breast to the lung in vivo. We show that invasion impairment is due to the inhibition of key effectors of the epithelial-mesenchymal transition. We have developed Lumifluor patient-derived xenograft models and assessed the effect of our inhibitors at various stages during the process of metastases. We have identified CK1δ as an efficacious therapeutic target with dual potential for triggering apoptosis of breast tumor cells and impairing metastatic spread from the primary tumor.

Citation Format: Bayle S, Lafitte M, Quereda V, Roush WR, Duckett DR. Targeting of casein kinase 1δ inhibits triple negative breast cancer metastasis [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-01-05.
Abstract P2-01-07: M2-like tumor-associated macrophages require Tartrate-resistant acid phosphatase as overall function to promote breast cancer metastasis
Authors: Dai M-S , Lo H-C , Chen L-C , Janckilla A , Tseng S-F
Published: May 2019

Tartrate-resistant acid phosphatase (TRAP) is a member of the purple acid phosphatase family and is also known as type 5 acid phosphatase. It is mainly expressed in cells of the monocyte lineage, including osteoclasts, macrophages, and dendritic cells (DCs). There are two isoforms of TRAP enzyme: TRAP-5a and TRAP5b, and TRAP-5b is produced by post-translational modification of TRAP-5a. TRAP-5b is the major isoform of TRAP secreted by osteoclasts and it has been shown that TRAP-5b activity correlates with the number of osteoclasts and serum activity in rat and human studies. In contrast, macrophages and DCs are thought to secrete TRAP-5a as the major subtype, whereas TRAP-5a is a non-specific marker of macrophage activation. The recent studies show that higher-grade proliferative tumors with much necrosis were associated with abundant macrophage expressing TRAP. Here we generate TRAP-/- knockout mice to study the function of TRAP in tumorigenesis. In vitro experiments have found that the expression of TRAP in macrophages is essential for the full promoting tumor function of M2-like tumor-associated macrophages (TAM) including tumor growth and metastasis. Marrow-derived macrophages (BMDM) extracted from the TRAP-/- mice lost promote tumor migration activity. The 4T1 tumor (murine breast cancer cell line) conditioned medium was used to induce TAM formation found M2-like TAM formation in wild type BMDM was promoted higher than that of TRAP-/- BMDM. In contrast, the TRAP-/- is much higher M1-like TAM formation than the wild type. Xenograft tumor formation assays were used to monitor tumor formation by combining 4T1 and different M2 polarized macrophages into BALB/c mice. M2-polarized macrophages with trap-defective BMDM showed reduced promoted neoplastic activity compared to wild type. In MMTV-PyMT transgenic mice, spontaneous tumor formation in knockout trap-/- significantly repressed tumor formation compared to TRAP+/+ wild type mice. Finally, we hypothesized that TRAP is essential for the full function of M2-like tumor-associated macrophages and promotes tumor metastasis.

Citation Format: Dai M-S, Lo H-C, Chen L-C, Janckilla A, Tseng S-F. M2-like tumor-associated macrophages require Tartrate-resistant acid phosphatase as overall function to promote breast cancer metastasis [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-01-07.
Abstract P2-01-10: Withdrawn
Authors: Hasan MK , Widhopf II GF , Zhang S , Shen Z , Briggs SP , Kipps TJ
Published: May 2019

This abstract was withdrawn by the authors.

Citation Format: Hasan MK, Widhopf II GF, Zhang S, Shen Z, Briggs SP, Kipps TJ. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-01-10.
Abstract P2-01-12: Detection of circulating cancer stem cells: A novel approach as a predictive marker for breast cancer metastases. This may be especially useful in patients with undetectable circulating epithelial tumor cells
Authors: Pizon M , Schott D , Pachmann U , Pachmann K
Published: May 2019

Background: Breast cancer is one of the most common types of cancer in women worldwide. It has been demonstrated that even localized tumors without clinically apparent metastases give rise to circulating epithelial tumor cells (CETCs). Recent studies have provided strong support for the circulating cancer stem cell (cCSC) hypothesis, which suggests that a more aggressive subpopulation of circulating tumor cells are the source of metastatic spread from the primary tumor. Measuring CETCs in blood of patients has emerged as a non-invasive diagnostic procedure for screening patients who may be at high risk for developing metastatic cancers. However, accurate detection of CETCs may provide erroneous results, since CETCs undergoing EMT during metastasis are down-regulated for the expression of epithelial cell markers.

Methods: 26 breast cancer patients were included into the study. The determination of CETCs and cCSC was performed using maintrac® method and tumorsphere forming assay, respectively. Cell viability, surface marker expression and ALDH 1 activity of the cells in the spheres were evaluated by fluorescence scanning microscope.

Results: Sphere formation was observed in 80 % of patients. We found that the number of tumorspheres depended on stage of disease. The number of tumorspheres increased significantly with tumor progression, especially with the presence of metastases. Tumorsphere formation was observed in all metastatic patients (median of 30 tumorspheres/100μl of blood), although only 27% of them had detectable CETCs. Analysis of surface marker expression profile showed that the cells in the spheres had typical phenotype of cancer stem cells. Sphere formation was not observed in healthy subjects (n=20).

Conclusion: There is a high correlation between the numbers of tumorspheres cultured from peripheral blood with clinical stage of disease. This may be an indicator of tumor aggressiveness, especially presence of metastases and may provide clinically useful prognostic information.

Citation Format: Pizon M, Schott D, Pachmann U, Pachmann K. Detection of circulating cancer stem cells: A novel approach as a predictive marker for breast cancer metastases. This may be especially useful in patients with undetectable circulating epithelial tumor cells [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-01-12.
Abstract P2-01-16: CRISPR-Cas9 screen identifies TMEM106A as a suppressor of breast cancer metastasis
Authors: Yang L , Yu S-J , Shao Z-M
Published: May 2019

Purpose: Breast cancer is one of the most common malignancies among women. The majority of cancer-associated deaths are caused by metastasis. Many biological alterations occur during this complex process, including the epithelial-mesenchymal transition (EMT), tumor immune escape, transendothelial migration (TEM). However, the biological mechanism of metastatic disease remains poorly understood and more need to be done to unify our understanding of underpinnings for metastasis in breast cancer.

Methods: We performed functional screening with CRISPR-Cas9 Genome-Scale CRISPR Knock-Out (GeCKO) library to identify metastasis-associated genes in breast cancer. We confirmed the function of a set of genes by transwell assays to testify the efficacy of in vivo screening. Further, we conducted in vitro and in vivo assays to explore the mechanism of TMEM106A in suppressing metastasis of breast cancer.

Results: The CRISPR-Cas9 library screening identified genes with potential of suppressing metastasis in breast cancer. Further validation of COPS2, SSBP2, TDG, DYRK4, GSG1, TMEM106A and PRR5L revealed that knock down of these genes promoted cell migration and invasion ability. In MDA-MB-231 and MDA-MB-468 cells, knock down of TMEM106A promoted in vitro migration, invasion, wound healing and in vivo pro-metastasis ability. In addition, E-cadherin was down-regulated and N-cadherin was up-regulated with suppression of TMEM106A. Accordingly, the potentiality of pro-metastasis was reversed when exogenous TMEM106A was expressed in MDA-MB-231 and MDA-MB-468 cells. We found the interaction between TMEM106A and WDR77 via Co-IP and MS analysis. Down-regulation of TMEM106A promoted expression of WDR77, which primarily occurred in the cytoplasm. To verify the association between TMEM106A and WDR77, we interfere WDR77 expression in MDA-MB-231 sg-TMEM106A, and the pro-metastasis effect of TMEM106A down-regulation was reversed.

Discussion: CRISPR-Cas9 library screening is an effective strategy to identify genes associated with breast cancer metastasis. The positive selection provides us a set of genes with potentiality to repress migration and invasion. TMEM106A may suppress metastasis via influencing translocation of WDR77 in breast cancer.

Citation Format: Yang L, Yu S-J, Shao Z-M. CRISPR-Cas9 screen identifies TMEM106A as a suppressor of breast cancer metastasis [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-01-16.
Abstract P2-01-21: Not presented
Authors: Hyder SM , Cook MT , Liang Y
Published: May 2019

This abstract was not presented at the conference.

Citation Format: Hyder SM, Cook MT, Liang Y. Not presented [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-01-21.
Abstract P2-01-23: Not presented
Authors: Xing W , Li Q , Cao R , Sun G , Jiang C
Published: May 2019

This abstract was not presented at the conference.

Citation Format: Xing W, Li Q, Cao R, Sun G, Jiang C. Not presented [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-01-23.
Abstract P2-01-24: Sulindac and triple negative breast cancer progression
Authors: Xi Y , Yi B , Riker A
Published: May 2019

In 2018, a total of 266,120 new cases and 40,920 deaths from breast cancer in the United States were estimated by the American Cancer Society. Breast cancer is the most common malignancy and the second leading cause of death among American women. In this study, we will focus on triple negative breast cancer (TNBC), which is viewed by oncologists as a problematic and unpredictable sub-category of breast cancer because of higher rates of recurrence and poorer prognosis. TNBC accounts for up to 20% of all breast cancers and is highly prevalent in minority and young women. On average, 70% of women with metastatic TNBC die within 5 years, regardless of chemotherapy or other treatments. As such, there is an urgent medical need to develop more effective drugs to manage this deadly disease that already raised a health disparity concern, especially in the State of Louisiana. Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used drugs for the treatment of pain, fever, and inflammation. Epidemiological studies have reported that the long term use of NSAIDs can prevent the occurrence multiple types of cancers, including breast cancer. However, their long term use for chemoprevention is not recommended because of toxicities associated with cyclooxygenase (COX) inhibition and the suppression of physiologically important prostaglandins. Our results show that the NSAID, sulindac sulfide (SS) and its non-COX inhibitory derivatives, can significantly inhibit the growth of the major subtypes of TNBC cells (basal-like, mesenchymal, and luminal). In addition, the compounds significantly inhibit tumor cell invasion. The animal experiments using Patient Derived Xenograft models supported the in vivo efficacy of these drugs. While studying the mechanism, we found that four oncogenic miRNAs, miR-10b, miR-17, miR-21, and miR-9 can be downregulated by SS and derivatives, and they were reported to promote tumor metastasis exclusively. Therefore, we conclude that those oncogenic miRNAs are involved in anti-metastatic activities of SS and its new non-COX inhibitory derivatives in TNBC.

Citation Format: Xi Y, Yi B, Riker A. Sulindac and triple negative breast cancer progression [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-01-24.
Abstract P2-02-02: The receptor tyrosine kinase EphA2 promotes glutamine metabolism in tumors by activating the transcriptional coactivators YAP and TAZ
Authors: Edwards DN , Ngwa VM , Wang S , Shiuan E , Brantley-Sieders DM , Kim LC , Reynolds AB , Chen J
Published: May 2019

Malignant tumors reprogram cellular metabolism to support cancer cell proliferation and survival. Although most cancers depend on a high rate of aerobic glycolysis, many cancer cells also display addiction to glutamine. Glutamine transporters and glutaminase activity are critical for glutamine metabolism in tumor cells, and upstream regulatory signaling pathways may represent a novel mechanism for targeted therapies in glutamine-addicted breast tumors such as Her2-overexpressing and triple-negative breast cancers (TNBC). We have found that the receptor tyrosine kinase EphA2 activated the transcriptional coactivators YAP and TAZ (YAP/TAZ), likely in a ligand-independent manner, to promote glutamine metabolism in cells and mouse models of breast cancer. Overexpression of EphA2 induced the nuclear accumulation of YAP and TAZ and increased the expression of YAP/TAZ target genes. Inhibition of the GTPase Rho or the kinase ROCK abolished EphA2-dependent YAP/TAZ nuclear localization. Silencing YAP or TAZ reduced the amount of intracellular glutamate through decreased expression of SLC1A5 and GLS, respectively, genes that encode proteins that promote glutamine uptake and metabolism. The regulatory DNA elements of both SLC1A5 and GLS contain the consensus sequence of the TEAD family of transcription factors that are closely associated with YAP/TAZ and were bound by TEAD4 in an EphA2-dependent manner. In patient breast cancer tissues, EphA2 expression positively correlated with that of YAP and TAZ, as well as that of GLS and SLC1A5. Although high expression of EphA2 predicted enhanced metastatic potential and poor patient survival, it also rendered breast cancer cells more sensitive to glutaminase inhibition. The findings define a previously unknown mechanism of EphA2-mediated glutaminolysis through YAP/TAZ activation in breast cancer and identify potential therapeutic targets in patients.

Citation Format: Edwards DN, Ngwa VM, Wang S, Shiuan E, Brantley-Sieders DM, Kim LC, Reynolds AB, Chen J. The receptor tyrosine kinase EphA2 promotes glutamine metabolism in tumors by activating the transcriptional coactivators YAP and TAZ [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-02-02.
Abstract P2-02-07: Targeting iron metabolism in breast cancer: Ferroptosis and genome stability
Authors: Possemato RL , Sviderskiy VO , Alvarez SW , Terzi EM
Published: May 2019

Iron-sulfur clusters are cell-essential protein cofactors in at least 48 human enzymes supporting diverse cellular functions, including genomic integrity and oxidative phosphorylation, and acting as molecular sensors for oxygen and iron levels. We recently described that breast cancer cells are particularly dependent upon robust iron-sulfur cluster biosynthesis for the survival of elevated oxygen conditions, including seeding lung metastases (1). Moreover, we found that even partially blocking cluster synthesis activated an iron-starvation response, rendering breast cancer cells susceptible to oxidative stress and death by ferroptosis (1). However, the precise mechanisms underlying these phenotypes remain to be fully elucidated. Here, we find that basal-like breast cancer cells are particularly susceptible to suppression of iron-sulfur cluster biosynthesis. By systematically evaluating proteins containing iron-sulfur clusters, we discovered that this susceptibility lies in the intrinsic vulnerability of basal-like breast cancer cells to genomic instability. These results have enabled us to define specific molecular targets in basal-like breast cancer which induce DNA damage, replication fork instability, and apoptosis, with striking subtype specificity. Our findings have broad implications for the underlying differences in genomic integrity in basal-like and luminal breast cancer subsets, and will inform future novel strategies to target genomic integrity in basal-like breast cancer.

1. Alvarez S, Sviderskiy VO, Terzi EM, Papagiannakopoulos T, Moreira AL, Adams S, Sabatini DM, Birsoy K, and Possemato R. NFS1 Undergoes Positive Selection in Lung Tumors and Protects Cells From Elevated Oxygen Levels and Ferroptosis, Nature. 2017 Nov 30;551(7682):639-643.

This work was supported by a Susan G. Komen Career Catalyst Award and the NCI (R01 CA214948).

Citation Format: Possemato RL, Sviderskiy VO, Alvarez SW, Terzi EM. Targeting iron metabolism in breast cancer: Ferroptosis and genome stability [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-02-07.
Abstract P2-02-10: Progesterone receptor membrane component-1 interacts with proteins of the cholesterol synthesis pathway resulting in altered cholesterol metabolism in breast cancer cells: Potential mechanism contributing to breast cancer progression
Authors: Ludescher M , Stamm N , Niederacher D , Ruckhäberle E , Fehm T , Neubauer H
Published: May 2019

Background: Progesterone Receptor Membrane Component-1 (PGRMC1) is upregulated in breast tumors and elevated expression of PGRMC1 is associated with increased tumor growth, indicating that PGRMC1 plays a role in carcinogenesis of breast cancer. However, the mechanism by which PGRMC1 contributes to breast cancer progression is not understood yet. Here we describe a potential mechanism by which PGRMC1 contributes to progression of breast cancer via deregulation of cholesterol synthesis and metabolization.

Methods: PGRMC1 interaction partners were identified by co-immunoprecipitation followed by mass spectrometry and validated using proximity ligation assay (PLA) in various breast cancer cell lines. To study how elevated PGRMC1 expression contributes to cholesterol balance, we generated PGRMC1 overexpressing breast cancer cells and determined levels of cholesterol-, lathosterol- and the cholesterol metabolite 27-hydroxycholesterol. Since 27-hydroxycholesterol is presumed to have estrogenic action, stimulating the growth of ER-positive breast cancer cells and limiting the effectiveness of aromatase inhibitors, we further investigated the activity of ERα in PGRMC1 overexpressing cell lines.

Results: Interaction of PGRMC1 with proteins involved in cholesterol synthesis, including Acyl-CoA desaturase (SCD), Squalene synthase (FDFT1) and Lanosterol 14-alpha demethylase (CYP51A1), was detected by mass spectrometry and verified by PLA. Elevated levels of cholesterol and its metabolites were detected in PGRMC1 overexpressing cells, suggesting a contribution of PGRMC1 to cholesterol synthesis and metabolization. Further, increased activity of ERα was found in PGRMC1 overexpressing cells, indicating activation of the receptor by cholesterol metabolites.

Conclusion: Cholesterol metabolism is involved in cancer cell proliferation as well as resistance to anti-cancer therapy. Our results indicate that elevated cholesterol metabolism induced by interaction of PGRMC1 with enzymes of the cholesterol biosynthesis pathway might contribute to malignant transformation and promote breast cancer progression. PGRMC1 might therefore present an interesting target for anti-cancer therapy.

Citation Format: Ludescher M, Stamm N, Niederacher D, Ruckhäberle E, Fehm T, Neubauer H. Progesterone receptor membrane component-1 interacts with proteins of the cholesterol synthesis pathway resulting in altered cholesterol metabolism in breast cancer cells: Potential mechanism contributing to breast cancer progression [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-02-10.
Abstract P2-02-16: Not presented
Authors: Li Y , Chu J , Li J , Tang J , Yin Y
Published: May 2019

This abstract was not presented at the conference.

Citation Format: Li Y, Chu J, Li J, Tang J, Yin Y. Not presented [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-02-16.
Abstract P2-06-04: Enhancing abiraterone acetate efficacy in androgen receptor-positive triple negative breast cancer: Chk1 as a potential target
Authors: Grellety T , Callens C , Richard E , Pulido M , Goncalves A , Gestraud P , MacGrogan G , Bonnefoi H , Cardinaud B
Published: May 2019

Purpose: Our aim was to identify predictive factors of abiraterone acetate (AA) efficacy and putative new druggable targets in androgen receptor (AR)-positive triple-negative breast cancer (TNBC) treated in the UCBG 2012-1 trial.

Material and methods: We defined AA response as either complete or partial response, or stable disease at 6 months. Using Ampliseq, we sequenced 91 general and breast cancerassociated genes from the tumor DNA samples. We analyzed transcriptomes from the extracted RNA samples on a Nanostring platform and performed immunohistochemistry (IHC) on tumor samples using tissue microarrays. We assessed AA and CHK1 inhibitors (GDC-0575 and AZD7762) efficacies, either alone or in combination, on cell lines grown in vitro and in vivo.

Results: Classical IHC apocrine markers, including AR, FOXA1, GGT1 and GCDFP15, allowed identifying AA responders and non-responders. All responders have clear apocrine features. Transcriptome analysis revealed that 31 genes were differentially expressed in the two subgroups, 9 of them being linked to proliferation and DNA damage repair. One of the most significant differences was the overexpression in non-responders of CHEK1, a gene encoding Chk1, a protein kinase that can be blocked by specific inhibitors. In vitro, AA and Chk1 inhibitor combination showed additive or slightly synergistic effect on cell viability, cell cycle, apoptosis and accumulation of DNA damages. In vivo, orthotopic xenograft experiments confirmed the efficacy of this combination therapy.

Conclusions: This study suggests that apocrine features can be helpful in the identification of AA-responders. We identified Chk1 as a putative drug target in AR-positive TNBCs.

Citation Format: Grellety T, Callens C, Richard E, Pulido M, Goncalves A, Gestraud P, MacGrogan G, Bonnefoi H, Cardinaud B. Enhancing abiraterone acetate efficacy in androgen receptor-positive triple negative breast cancer: Chk1 as a potential target [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-06-04.
Abstract P2-06-14: The role of SLC7A5 (LAT1) in endocrine therapy-resistant breast cancer
Authors: Sevigny CM , Sengupta S , Luo Z , Jin L , Pearce D , Clarke R
Published: May 2019

Endocrine therapies are commonly used to treat estrogen receptor-positive (ER+) breast cancers, which comprise 70% of all new breast cancer cases. Unfortunately, emergence of resistance to these therapies presents a major clinical challenge. Cancer cells can adapt to the dysregulation of cellular metabolism induced by endocrine therapy in order to evade cell death.Central to this adaptation is the scavenging of free-formed amino acids from the tumor microenvironment. For example, we found 109 solute carrier (SLC) mRNAs to be differentially expressed between endocrine-sensitive and resistant cells. We began our mechanistic studies of these genes with SLC family 7 member 5 (SLC7A5 or LAT1). SLC7A5 is a key component of a transmembrane transporter, which can complex with CD98 and increase the uptake of large, neutral amino acids (such as leucine or tyrosine).

We used a panel of endocrine therapy-resistant (LCC9) and sensitive (MCF7; LCC1) breast cancer cells. SLC7A5 expression was upregulated by estrogen in MCF7 and LCC1 cells; this induction was blocked by fulvestrant treatment. Basal expression of the SLC7A5 protein in the absence of estrogen was 2.75-fold higher in LCC9 cells compared with MCF7 cells; SLC7A5 mRNA expression was 71-fold higher. Fulvestrant treatment did not significantly alter SLC7A5 mRNA or protein expression in LCC9 cells. Inhibiting SLC7A5 function using either a pharmacological inhibitor (JPH203), or depleting expression using siRNA, led to significant suppression of LCC9 cell growth. Cell cycle analysis revealed that SLC7A5 depletion caused cells to accumulate in the G1-phase, with a concurrent reduction of cells in S-phase. In four publicly available datasets of ER+, tamoxifen treated breast cancer patients, high expression of SLC7A5 was significantly associated with poor relapse-free survival.

This study uncovers a novel adaptive mechanism in endocrine therapy-resistant breast cancer cells that is facilitated by increased expression of SLC7A5, which enables them to supplement their increased metabolic needs and promoting cell growth. Blocking the functions of SLC7A5, perhaps in conjunction with inhibition of autophagy, may therefore offer a new avenue of potential therapeutic intervention against endocrine therapy-resistant breast cancers.

Citation Format: Sevigny CM, Sengupta S, Luo Z, Jin L, Pearce D, Clarke R. The role of SLC7A5 (LAT1) in endocrine therapy-resistant breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-06-14.
Abstract P2-06-21: Endogenous expression of ERβ variants contributes towards chemotherapy-resistance in the triple negative breast cancer cell line HCC-1806
Authors: Faria M , Gustafsson J-A , Strom A
Published: May 2019

Triple negative breast cancer (TNBC) still remains a challenge to treat in the clinic due to a lack of good targets for treatment. Although TNBC lacks expression of ERα, the expression of ERβ and its variants are detected quite frequently in this cancer type and can represent an avenue for treatment. We show that the variants of ERβ, namely ERβ1, ERβ2, ERβ4, and ERβ5, contributes to aggressiveness of the TNBC cell line HCC1806 by affecting E-Cadherin expression and chemotherapy sensitivity.

We have previously shown that the HCC1806 cell line expresses all the ERβ variants. To investigate their function we used the recently developed dCas9-KRAB system with Guide RNA for both ERβ promoters 0N and 0K, using 3 guide RNA's for each promoter and we found that expression of panERβ decreased from a ct. of 28 to 33 indicating loss of total ERβ. Treatment of HCC1806 cells with chemotherapy in combination with an ERβ agonist, LY500307, is more effective in reducing cancer cell viability. Knockdown of total ERβ in HCC1806 cells using CRISPR-Cas9 technology, decreased the proliferation and increased chemo-sensitivity to docetaxel agent in cells with the 0K promoter knock down, while cells with the 0N promoter knock down were less affected. Furthermore, after ERβ knockdown, the cell morphology of HCC-1806 changed to a more epithelial phenotype and there was increase in the expression of the classical epithelial marker, E-cadherin. N-Cadherin was unchanged in the cells with the 0K promoter knock down, while E-Cadherin was slightly decreased in cells with the 0N promoter knock down. We also found that cells with the 0K promoter knock down migrated less than control cells in a migration assay, while cells with the 0N promoter knock down were less affected. These findings are in agreement with reports showing that the 0K promoter is responsible for expression of the variants ERβ2 and ERβ5, while the 0N promoter expresses more ERβ1. Furthermore, we have earlier shown that ERβ2 and ERβ5 increase aggressiveness of TNBC via several oncogenic signaling pathways.

In conclusion, knockdown of ERβ variants in HCC-1806 indicated that the variants may be responsible for conferring oncogenic properties to TNBC such as EMT, cancer cell proliferation and chemo-resistance. Therefore, treating TNBC patients with combination therapy including ERβ agonists, may prove to be extremely beneficial for securing better treatment responses and future pre-clinical studies should design appropriate experiments to confirm these findings in vivo.

Citation Format: Faria M, Gustafsson J-A, Strom A. Endogenous expression of ERβ variants contributes towards chemotherapy-resistance in the triple negative breast cancer cell line HCC-1806 [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-06-21.
Abstract P2-07-12: A prognostic prediction nomogram (PDIDC) for breast Paget's disease with infiltrating ductal carcinoma patients: A SEER cohort analysis
Authors: Tan L , Chen K , Jiang WG , You N , Wang Y , Sanders A , Liang G , Liu Z , Ling Y , Zhong W , Tian Z , Gong C
Published: May 2019

Purpose

The aim of the study was to develop a specific nomogram for prediction of prognosis for breast Paget's disease with infiltrating ductal carcinoma (PD-IDC) patients.

Patients and Methods

Patients data were obtained by the Surveillance, Epidemiology, and End Results (SEER) program (N=2502). Study outcome was Breast Cancer Specific Survival (BCSS). Cox proportional hazards model was applied to identify risk factors and develop predictive model. For internal validation, discrimination was calculated with the concordance index (C-index) using the bootstrap method and calibration assessed.

Results

NPI classification, skin symptom, tumor site and age showed significant association with BCSS(table.1)and were used to build the PDIDC nomogram and to calculate risk score. PDIDC nomogram's C-index (0.791, 95%CI 0.783-0.818) showed better discrimination power than NPI classification (0.691, 95%CI, 0.650-0.735, P= 0.000) and AJCC staging (0.718, 95%CI, 0.695-0.741, P=0.000). Patients were divided into high-risk (1882/2502, 75.21%) and low-risk (620/2502, 24.78%) subgroups with the optimal cut-off of risk scores (4.28). The total BCSS of low-risk subgroup was 77.8% (95%CI 74.4%-81.4%) vs. 31.1% (95%CI 19.4-49.8) of high-risk group (P=0.000). Bootstrap internal validation demonstrated an average C-index of 0.739 (95% CI, 0.692-0.746). The nomogram calibration was validated to be accurate in predicting 5-year and 10-year survival.

Variable finally selected for risk predicted model.PredictorHazard RatioP Value95% CINPI classification Good1 Moderate2.170.0001.51-3.14Poor7.260.0004.96-10.63Skin symptom Without1 With1.760.0001.34-2.32Tumor site Centrally located1 Non-centrally located1.250.0421.07-1.56Age*1.010.0001.01-1.03* Continuous variable.

Conclusion

Utilizing NPI classification, skin symptom, tumor site and age, we developed the PDIDC nomogram to predict the 5-year and 10-year BCSS of breast PD-IDC patients.

Citation Format: Tan L, Chen K, Jiang WG, You N, Wang Y, Sanders A, Liang G, Liu Z, Ling Y, Zhong W, Tian Z, Gong C. A prognostic prediction nomogram (PDIDC) for breast Paget's disease with infiltrating ductal carcinoma patients: A SEER cohort analysis [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-07-12.
Abstract P2-08-45: Malic enzyme 1 is a potential metastasis-related biomarker of breast cancer
Authors: Liu C , Tao Z , Hu X
Published: May 2019

Background: Malic enzyme 1 (ME1) catalyzes malate to pyruvate and thus promotes glycolysis, playing a part in the Warburg effect. Recently, several researches have revealed its crucial role in cancer metastasis. KM-plotter, an online analysis tool, showed high ME1 mRNA level was related to poorer RFS and OS. Herein, we explore the prognostic effect of ME1 on invasive breast cancer in Chinese patients and its effect on metastasis in vitro.

Methods: 220 patients with early breast cancer were included in this study. ME1 expression was evaluated semi-quantitatively with tissue microarray-based immunohistochemistry. The relationships between ME1 expression level and clinicopathological features were explored. Survival analyses were carried out by Kaplan-Meier test and COX proportional hazard model. MCF-7 and MDA-MB-468 cell lines were then used for in vitro cell migration and invasion assays.

Results: High expression of ME1 was observed in 51.5% patients. The median follow-up period was 28.9 months (range 0.5-34.0). In correlation analyses, compared with ME1-low cases, ME1-high cases were significantly associated with larger tumor size (P=0.036), positive lymph nodes (P<0.001) and positive lymph-vascular invasion (P=0.003), and tended to be HER2 positive (P=0.094). Survival analysis by Kaplan-Meier test showed high ME1 expression was significantly correlated with poorer recurrence free survival (RFS) (P=0.015). Multivariate analysis identified high ME1 expression as an independent prognostic factor for RFS (P=0.035, HR=5.072 [1.121, 22.942]). Stratified analysis revealed high ME1 expression was related to poorer RFS among cases more than 45 years old (P=0.029, HR=9.833 [1.269, 76.164]) and among those with Ki67 index ≥20% (P=0.038, HR=3.805 [1.074, 13.486]). In vitro, HER2 positive cell line (SKBR3) and TNBC cell lines (MDA-MB-231, MDA-MB-468) showed high expression of ME1, while luminal cell line (MCF-7) showed low expression of ME1. Upregulation of ME1 in MCF-7 cell line remarkably enhanced its ability in migration and invasion, while knockdown of ME1 in MDA-MB-468 cell line had a profound inhibitory effect on migration and invasion.

Conclusions: ME1 enhances migration and invasion of breast cancer cell lines and may be involved in early development of breast cancer metastasis. Thus, ME1 is a promising prognostic indicator and a potential therapeutic target.

Citation Format: Liu C, Tao Z, Hu X. Malic enzyme 1 is a potential metastasis-related biomarker of breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-08-45.
Abstract P2-08-50: Elevated levels of serum tumor marker p53 is a prognostic parameter and a monitoring biomarker for patients who had undergone surgical resection in breast cancer
Authors: Arai M , Nagata T , Sekine S , Baba H , Moriyama M , Hashimoto I , Fujii T
Published: May 2019

Background

Elevated levels of serum tumor maker p53 antibody is expected as an indicator of early diagnosis and a parameter of recurrence in breast cancer. P53 mutation accounts for 20% to 35% in all breast cancer patients. Preoperative high level of anti-p53 antibody in breast cancer patients tend to associate with worse prognosis. This study investigated the prognostic value of preoperative serum p53 levels, and the significance as a biomarker to evaluate a recurrence after surgical resections in breast cancer.

Methods

Preoperative serum p53 concentration levels were measured in total of 259 breast cancer patients, who had undergone either a total mastectomy or a partial mastectomy, through 2010 to 2015 in our facility. Patients with elevated levels of p53 (29 patients) and normal levels of p53 (230 patients) were compared to analyze the association of a marker level with the prognosis and the indication to diagnose recurrence in breast cancer.

Results

Elevated serum level of p53 mutation was identified in 29 (11%) patients. The size of tumor, staging, and pathology did not associate with the level of p53. Patients with elevated serum level of p53 correlated to the high score of nuclear grade (NG2 and NG3) and the high percentage of Ki-67 (>14%), which leading to the worse prognosis. Triple negative breast cancer was the major molecular subtype in the group of high level of p53 comparing with the group of low level of p53. Survival analysis using the Kaplan-Meier method were performed to examine DFS and OS of high serum level of p53 patients. Patients with high level of p53 were significantly showed worse DFS than a normal p53 group. Serum level of p53 was also reflected to the recurrence and metastasis of postoperative breast cancer. There were three patients, who had local recurrences and metastasis, in the group of high levels of p53. Their serum levels of p53 were re-elevated as emerging the local recurrence and metastasis once they had gotten the normal serum levels of p53 after surgical resections. It showed that the increasing of the level of p53 was reflected to the recurrence and metastasis of tumors after surgical resections in breast cancer.

Conclusions

This study suggests that preoperative serum level of p53 can be an independent prognostic parameter and a monitoring biomarker for breast cancer.

Citation Format: Arai M, Nagata T, Sekine S, Baba H, Moriyama M, Hashimoto I, Fujii T. Elevated levels of serum tumor marker p53 is a prognostic parameter and a monitoring biomarker for patients who had undergone surgical resection in breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-08-50.
Abstract P2-08-56: Effects of young age on prognosis in patients with node-negative tumors 2 cm or smaller breast cancer
Authors: Zhong W , Tan L , You N , Wang Y , Liang G , Liu Z , Ling Y , Tian Z , Gong C
Published: May 2019

Background It is still controversial to consider age as a prognostic factor into the treatment strategy of patients with T1N0M0 breast cancer.

Aim The main purpose of this study was to evaluate the effect of age on recurrence risk in patients diagnosed with T1N0M0 breast cancer as well as compare the prognosis of young aged patients(YA,≤40 years old) to non-young aged patients(non-YA,>40 years old) by using a propensity score matching(PSM) analysis.

Methods 365 patients with T1N0M0 breast cancer diagnosed between 2003 and 2016 who received surgery in Sun Yat-sen Memorial Hospital Breast Cancer Center were included.The recurrence free survival (RFS) and risk factors for recurrence were identified by using Kaplan-Meier method and Cox proportional hazards models. PSM was then used to reduce the confounding effect of known risk factors on prognosis and then to compare 5-year RFS rates in patients between two age groups.

Results After a median follow up of 79 months, 54 patients developed recurrences and 5-year RFS was 87.6%. YA patients had lower RFS estimates (80.6%), compared to patients diagnosed in a later age (89.1% if older than 40-years old; P = 0.049). YA patients tended to have Her-2 positive, TNBC tumors, higher rate of Ki-67 expression and nuclear grade tumor. At multivariate analysis, Her-2 positive (HR 2.115; 95% CI 1.103-4.055, p=0.024) and TNBC (HR 2.963; 95% CI 1.485-5.914, p=0.002) resulted independent prognostic factors of patient with T1N0M0 breast cancer. In the subgroup analysis, we found significant poor RFS for YA patients with Her-2 positive breast cancer compared to the older counterparts(p=0.006) and YA patients were associated with significantly higher rates of the locoregional recurrence rather than metastasis(p=0.004), especially in first 5 years after diagnosis. After PSM, the baseline level and treatment status including tumor size, grade, HR status, Her-2 status, Ki67 expression breast surgery type and systemic adjuvant treatment(AST) of patients in the two age groups tended to be equal. As result, we found significant difference in the 5-year RFS between two age groups(p=0.008).

Conclusion Based on equal treatment condition, young age at presentation conferred a worse prognosis in patients with T1N0M0 breast cancer is independent on other pathological features.

Citation Format: Zhong W, Tan L, You N, Wang Y, Liang G, Liu Z, Ling Y, Tian Z, Gong C. Effects of young age on prognosis in patients with node-negative tumors 2 cm or smaller breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-08-56.
Abstract P2-08-60: Withdrawn
Authors: Lee S , Ahn SH , Son BH , Lee JW , Chung IY , Ko BS , Kim HJ , Kim J , Shon G
Published: May 2019

This abstract was withdrawn by the authors.

Citation Format: Lee S, Ahn SH, Son BH, Lee JW, Chung IY, Ko BS, Kim HJ, Kim J, Shon G. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-08-60.
Abstract P2-08-62: Not presented
Authors: Osman MH
Published: May 2019

This abstract was not presented at the conference.

Citation Format: Osman MH. Not presented [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-08-62.
Abstract P2-09-16: CD8 T cells induced by novel alphaviral vector predict improved progression free survival in advanced HER2+ breast cancer patients
Authors: Crosby EJ , Gwin WR , Chang S , Maecker HT , Lubkov V , Snyder JC , Broadwater G , Hyslop T , Osada T , Hobeika AC , Hartman ZC , Morse MA , Lyerly HK
Published: May 2019

Background: Immune-based therapy for metastatic breast cancer has had limited success. Strategies to augment adaptive immunity include vaccines targeting genomic amplifications like Human Epidermal Growth Factor Type 2 (HER2), an established driver of malignancy. Using a novel alphaviral vector, we constructed a vaccine encoding a portion of HER2 (VRP-HER2).

Methods: In preclinical studies, mice were immunized before or after implantation of hHER2+ tumor cells and HER2-specific immune responses and anti-tumor function were assessed. We then translated this vaccine into a phase I clinical trial in which subjects with advanced HER2-overexpressing breast cancers received VRP-HER2 every 2 weeks for a total of three doses (cohort 1). In cohort 2, subjects received the same dose of VRP-HER2 along with a standard HER2 targeted therapy.

Results: VRP-HER2 induced HER2-specific T cell and antibody responses while controlling tumor growth in murine models. Vaccination with VRP-HER2 was well tolerated in both patient cohorts. PFS was modest, while median OS was 50.2 months in cohort 1 and 32.7 months in cohort 2. In cohort 2, there is one partial response and two patients with continued stable disease. Vaccine induced anti-HER2 antibodies and T cells were identified. Increased perforin expression by memory CD8 T cells post vaccination significantly correlated with improved PFS.

Conclusions: VRP-HER2 led to an increase in perforin expressing HER2-specific memory CD8 T cells in preclinical and clinical studies, and had profound antitumor effects in murine models. The generation of HER2-specific memory CD8 T cells was significantly correlated with increased PFS in patients. Subsequent studies will seek to enhance T cell activity by combination with anti-PD-1/PD-L1 antibodies.

Citation Format: Crosby EJ, Gwin WR, Chang S, Maecker HT, Lubkov V, Snyder JC, Broadwater G, Hyslop T, Osada T, Hobeika AC, Hartman ZC, Morse MA, Lyerly HK. CD8 T cells induced by novel alphaviral vector predict improved progression free survival in advanced HER2+ breast cancer patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-09-16.
Abstract P2-13-05: Prevalence of trastuzumab-induced cardiotoxicity in a real-world setting
Authors: Calvillo-Argüelles O , Flores-Diaz D , Gonzalez-Serrano J-P , López-Rojas A , Mendoza-Galindo L , Matus-Santos J-A , Reynoso-Noverón N , Cabrera-Galeana P , Bargalló-Rocha E , Arce-Salinas C
Published: May 2019

Background: Trastuzumab treatment plus adjuvant or neoadjuvant chemotherapy is the standard of care for women with HER2 positive breast cancer. Despite relative low rates of cardiotoxicity observed in randomized clinical trials, trastuzumab interruption driven by LVEF reduction is a major concern in current clinical practice.

Patients and methods: We retrospectively identified women with stage I-III HER2 positive breast cancer who received 12 months of trastuzumab treatment after adjuvant or neoadjuvant chemotherapy at Instituto Nacional de Cancerología (INCan, Mexico City), between 2006 and 2018. Patients were eligible if a pre-therapy MUGA scan and ≥2 subsequent follow-up scans were available. Cardiotoxicity was defined as a ≥10% LVEF reduction to a value < 50%, associated with trastuzumab interruption.

Results: 910 patients were included, with a median age at diagnosis of 50 (24-85) years and a median follow up of 7 (2-11 ) years. Among the whole cohort, 10.3% of patients had diabetes, 15.4% had hypertension, 78% were obese/overweight, and 40% had positive estrogen and/or progesterone receptor status. Anthracycline-based therapy was used in 819 (90%) patients, with a median (doxorubicin equivalent) cumulative dose of 200 mg/m2 (IQR 180-240). The median baseline LVEF was 61.8% (50-88.9). In total, 94 (10.3%) patients developed cardiotoxicity, but symptomatic heart failure was observed in only 31 (3.4%) individuals. In univariable analyses, the development of cardiotoxicity was not associated significantly with cardiovascular risk factors.

Conclusions: In this large single-center cohort, cardiotoxicity rates remain high, thus, interventions to minimize the risk of cardiotoxicity and trastuzumab treatment interruption should be considered.

Citation Format: Calvillo-Argüelles O, Flores-Diaz D, Gonzalez-Serrano J-P, López-Rojas A, Mendoza-Galindo L, Matus-Santos J-A, Reynoso-Noverón N, Cabrera-Galeana P, Bargalló-Rocha E, Arce-Salinas C. Prevalence of trastuzumab-induced cardiotoxicity in a real-world setting [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-13-05.