bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P4-11-02: Subjective and objective assessment of efficacy of frozen gloves and socks to prevent nab-paclitaxel-induced peripheral neuropathy in patients with breast cancer
Authors: Yamashita T , Hattori M , Nakada T , Hayashi T , Kamei K , Tatsuya T , Nagao Y , Mase T , Wada M , Mizuno T , Shimozuma K , Iwata H , Yamaguchi T
Published: May 2019

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent side-effect of taxanes which play a central role in the treatment of breast cancer. CIPN can negatively influence long-term quality of life, warranting the development of effective prevention strategies. This study investigates the efficacy of frozen gloves and socks (FGS) in reducing the incidence and severity of nab-paclitaxel-induced peripheral neuropathy. Endpoints were evaluated using both clinician and patient reports.

Methods: This is a multicenter phase II single arm trial study of the effects of FGS for advanced or metastatic breast cancer patients receiving nab-paclitaxel (260 mg/m2) every 3 weeks. Patients wore FGS on their diseased side hand and foot for 60 min during infusion. The other side acted as the untreated control. CIPN was assessed using Patient Neurotoxicity Questionnaire (PNQ), PRO-CTCAE and CTCAE at baseline and every cycle of nab-paclitaxel. The primary endpoint was the incidence of CIPN assessed by PNQ (grade C or higher) after receipt of up to 4 cycles of nab-paclitaxel.

Results: Between September 2012 and January 2015, 50 patients from 16 sites were enrolled in this study. Of 50 patients, 27 (54%) received at least 4 cycles of nab-paclitaxel. There was a trend for the incidence of CIPN assessed by PNQ and PRO-CTCAE to be lower in the intervention side than in the control side, although this difference was not statistically significant. The incidence of CIPN assessed by CTCAE was significantly lower in the treated hand (Table).

Conclusions: Among breast cancer patients who received nab-paclitaxel, FGS produced favorable effects as detected by reduced clinician-reported CTCAE grades for CIPN, although the study did not detect differences in self-reported symptoms of CIPN using PRO-CTCAE or PNQ. Clinical trial information: UMIN000007907.

Difference according to the evaluation method of CIPN   Hands (%)  Feet (%)   InterventionControlp*InterventionControlp*Patient-Reporting CIPNPNQ (grade C or higher)12190.3416160.63Patient-Reporting CIPNPRO-CTCAE       Severity ≥ Moderate13180.0815160.56 Interference ≥ Somewhat7100.328100.32Clinician-Grading CIPNCTCAE (≥ Grade II)15190.0314131.0

*McNemar's test

Citation Format: Yamashita T, Hattori M, Nakada T, Hayashi T, Kamei K, Tatsuya T, Nagao Y, Mase T, Wada M, Mizuno T, Shimozuma K, Iwata H, Yamaguchi T. Subjective and objective assessment of efficacy of frozen gloves and socks to prevent nab-paclitaxel-induced peripheral neuropathy in patients with 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 P4-11-02.
Abstract P5-04-18: ARV-471, an oral estrogen receptor PROTAC degrader for breast cancer
Authors: Flanagan JJ , Qian Y , Gough SM , Andreoli M , Bookbinder M , Cadelina G , Bradley J , Rousseau E , Willard R , Pizzano J , Crews CM , Crew AP , Taylor I , Houston J
Published: May 2019

ARV-471, an estrogen receptor (ER) alpha PROTAC, is a hetero-bifunctional molecule that facilitates the interactions between estrogen receptor alpha and an intracellular E3 ligase complex, leading to the ubiquitylation and subsequent degradation of estrogen receptors via the proteasome. ARV-471 robustly degrades ER in ER-positive breast cancer cell lines with a half-maximal degradation concentration (DC50) of ˜ 2 nM. PROTAC-mediated ER degradation decreases the expression of classically-regulated ER-target genes (PR, GREB1, TFF) and inhibits cell proliferation of ER-dependent cell lines (MCF7, T47D). Additionally, ARV-471 degrades clinically-relevant ESR1 variants (Y537S and D538G) and inhibits growth of cell lines expressing those variants. In an immature rat uterotrophic model, ARV-471 degrades rat uterine ER and demonstrates no agonist activity. Daily, oral-administration of single agent ARV-471 (3, 10, and 30 mpk) leads to significant tumor volume regressions of estradiol-dependent MCF7 xenografts and concomitant tumor ER protein reductions of >90% at study termination. Moreover, when a CDK4/6 inhibitor is combined with ARV-471 in the MCF7 model, even more pronounced tumor growth inhibition is observed (˜130% TGI), accompanied by significant reductions in ER protein levels. In an ESR1 Y537S, hormone-independent patient-derived xenograft model, ARV-471 at 10 mpk completely inhibited growth and also reduced mutant ER protein levels. Taken together, the preclinical data of ARV-471 supports its continued development as a best-in-class oral ER PROTAC-degrader.

Citation Format: Flanagan JJ, Qian Y, Gough SM, Andreoli M, Bookbinder M, Cadelina G, Bradley J, Rousseau E, Willard R, Pizzano J, Crews CM, Crew AP, Taylor I, Houston J. ARV-471, an oral estrogen receptor PROTAC degrader for 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 P5-04-18.
Abstract P5-06-02: Organochlorine pesticide residues in human breast tissue and their relationships with clinical and pathological characteristics of breast cancer
Authors: Ellsworth RE , Kostyniak PJ , Chi L-H , Shriver CD , Costantino NS , Ellsworth DL
Published: May 2019

Agricultural pesticides are abundant environmental contaminants worldwide, prompting interest in studying their possible detrimental health effects. We examined organochlorine residues by quadrant (n = 245) in breast adipose tissues from 51 women with various stages of breast health to determine patterns of bioaccumulation within the breast and to assess relationships with patient clinical characteristics. Three organochlorine residues — 2,2-bis(p-chlorophenyl)-1,1-dichloroethylene (p,p′-DDE), hexachlorobenzene (HCB), and mirex — assayed by high resolution gas chromatography were abundant in breast tissue. p,p′-DDE (745 ± 1054 ng/g lipid) was the most prevalent residue, comprising 97.5% of the total chemical burden. Mean levels of p,p′-DDE and HCB were significantly correlated (P < 0.001) with patient age at mastectomy, and levels of p,p′-DDE were correlated (P < 0.05) with BMI. Pesticide concentrations did not differ significantly by breast quadrant and were not different in the quadrant(s) where the primary tumor was located compared to other cancer-free quadrants. In invasive cancer patients, organochlorine levels differed significantly based on clinical characteristics of the primary carcinoma, including stage, grade, ER status, and HER2 status, indicating that body burden of organochlorines may influence the development of specific subtypes of breast cancer. Potentially carcinogenic organochlorines were present at high levels within the human breast warranting further research to determine the impact of organochlorines in the etiology of breast cancer.

The opinions or assertions contained herein are the private ones of the author/speaker and are not to be construed as official or reflecting the views of the Department of Defense, the Uniformed Services University of the Health Sciences or any other agency of the U.S. Government.

Citation Format: Ellsworth RE, Kostyniak PJ, Chi L-H, Shriver CD, Costantino NS, Ellsworth DL. Organochlorine pesticide residues in human breast tissue and their relationships with clinical and pathological characteristics 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 P5-06-02.
Abstract P5-07-03: Small molecule inhibition of smoothened in triple negative breast cancer-associated fibroblasts depletes cancer stem cells and sensitizes to cytotoxic chemotherapy in mice and humans
Authors: Swarbrick A , Cazet A , Hui M , O'Toole S , Lim E , Martin M
Published: May 2019

The cellular and molecular basis of stromal cell recruitment, activation and crosstalk in carcinomas is poorly understood, limiting the development of targeted anti-stromal therapies.

In mouse models of triple negative breast cancer (TNBC), we use single cell genomics to show that Hh ligand produced by neoplastic cells reprograms cancer-associated fibroblast (CAF) gene expression, driving tumor growth and metastasis. Hh-activated CAFs upregulated expression of FGF5 and deposition of fibrillar collagen, leading to FGFR and FAK activation in adjacent neoplastic cells and the acquisition of a stem-like, drug-resistant phenotype.

Treatment with smoothened inhibitors (SMOi) reversed these phenotypes. Stromal treatment of TNBC patient-derived xenograft (PDX) models with SMOi downregulated the expression of cancer stem cell markers and sensitized tumors to docetaxel, leading to markedly improved survival and reduced metastatic burden.

In the phase I clinical trial EDALINE, 3 patients with metastatic TNBC derived clinical benefit from combination therapy with the SMOi Sonedigib and docetaxel chemotherapy, with one patient experiencing a complete radiological response. Responders also exhibited high baseline FGFR activation and ECM deposition, suggesting a mechanism of action consistent with findings from the animal models.

These studies identify Hh signaling to CAFs as a novel mediator of cancer stem cell plasticity and drug resistance and an exciting new therapeutic target in TNBC.

Citation Format: Swarbrick A, Cazet A, Hui M, O'Toole S, Lim E, Martin M. Small molecule inhibition of smoothened in triple negative breast cancer-associated fibroblasts depletes cancer stem cells and sensitizes to cytotoxic chemotherapy in mice and humans [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 P5-07-03.
Abstract P5-07-15: Adipose-derived peptides from breast cancer patients promote the malignancy of breast cancer MCF-7 cells
Authors: Fu Z , Li W , Wu H , Huang X , Li J , Sun C , Tang J , Yin Y
Published: May 2019

Adipose stromal/stem cells (ADSCs) could regulate malignancy behaviors of breast cancer, which was due to adipose-derived cytokines in part, such as leptin and resistin. Recently, peptides have been demonstrated to be potential targets for cancer therapy. It's valuable to analyze the characters of adipose-secreted peptides systematically. In this study, we isolated primary adipocytes from adipose tissue adjacent to breast tumor and breast benign lesions respectively, and then co-cultured breast cancer cells MCF-7 with tumor adjacent adipocytes (TAAs)/breast benign adipocytes (BBAs) separately. Compared to BBAs, TAAs could promote proliferation and migration ability of MCF-7. Then we extracted and purified peptides from supernatant of TAAs and BBAs using ultrafiltration, and the effects of TAAs-derived peptides compound on breast cancer cells appeared accordance with the adipose cells. 100 peptides, which were derived from 90 protein precursors, were found to be differentially secreted between TAAs and BBAs by LC-MS/MS (p < 0.05). Gene Ontology (GO) and Pathway analyses appeared that these altered peptides were mainly contributed to cell adhesion, and regulation of Ras-protein signal transduction. These results showed that these differentially secreted peptides could regulate breast cancer cell malignancy, which indicated that they could be potential therapeutic targets and diagnostic bio-marker for breast cancer.

Citation Format: Fu Z, Li W, Wu H, Huang X, Li J, Sun C, Tang J, Yin Y. Adipose-derived peptides from breast cancer patients promote the malignancy of breast cancer MCF-7 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 P5-07-15.
Abstract P5-18-10: BHLHE40-AS1 is an enhancer associated long noncoding RNA critical to breast cancer progression
Authors: DeVaux RS , Schimjawicz H , Coarfa C , Behbod F , Herschkowitz JI
Published: May 2019

Increased emphasis on breast cancer screening has led to a dramatic increase in diagnosis of ductal carcinoma in situ (DCIS). DCIS lesions are nonobligate precursors of invasive ductal carcinoma (IDC) and thus, the current standard-of-care is aggressive therapy to prevent invasive and metastatic disease. However, only ˜40% of DCIS cases are predicted to progress leading to a current state of overtreatment and overdiagnosis. Thus, there is a critical need to identify functional determinants of progression of DCIS to IDC to allow discrimination between indolent and aggressive breast cancers and refine patient treatment strategies.We propose that long noncoding RNAs (lncRNAs) functionally drive breast cancer progression and their expression can discriminate between innocuous and potentially invasive DCIS.

Using biopsies from women with tandem DCIS and IDC lesions, we identified 35 lncRNAs whose expression can distinguish between pre-invasive and invasive disease. From this candidate list, the lncRNA BHLHE40-AS1 is found enriched in multiple breast cancer progression models, in HER2+ cell lines, and HER2+ patient tumors. Functionally, BHLHE40-AS1 is found to support tumor cell cycle and motility and may serve as a clinically relevant biomarker and therapeutic target in invasive breast cancer.

Further, BHLHE40-AS1 is expressed from a known super-enhancer that preliminary evidence suggests undergoes altered chromatin looping during breast cancer progression. Interestingly, over half of the candidate lncRNAs are associated with enhancer regions. Current studies are investigating super-enhancers, and associated lncRNAs that become acquired during breast cancer progression.

Citation Format: DeVaux RS, Schimjawicz H, Coarfa C, Behbod F, Herschkowitz JI. BHLHE40-AS1 is an enhancer associated long noncoding RNA critical 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 P5-18-10.
Abstract P6-18-34: Treat ER+ight Canadian prospective observational study in HR+ advanced breast cancer: 3rd interim analysis
Authors: Doyle C , Califaretti N , Dent S , Iqbal N , Mates M , Kulkarni S , Bains P , Glenns V , Perri SR , Chia S
Published: May 2019

Treat ER+ight is the 1st prospective observational study in Canadian HR+ HER2– advanced breast cancer patients currently receiving endocrine therapy (ET) alone or in combination with targeted therapy (TT) in the first, second or third line setting (NCT02753686).

Methods: This pre-planned interim analysis describes baseline characteristics, treatment patterns and safety/toxicity of patients enrolled in ET and ET+TT cohorts. At data cut-off (November 2017), 200 patients were enrolled from 24 sites since March 2016. The median follow-up time at data cut-off was 8.1 months and 182 patients were evaluable for this analysis.

Results:

 ET (n=73)ET + TT (n=109)Baseline Patient and Disease Characteristics  Median age, years (range)71 (37-92)65 (39-87), p=0.017ECOG 0-1 (%)6274Median time since primary BC diagnosis, years (range)5 (0-37)6 (0-31)Median time with advanced BC diagnosis, years (range)1 (0-16)1 (0-8)Sites of Metastases (%)  Bone only4027Visceral6073Location of Metastases (%)  Lungs5747Liver2348, p=0.006Bone4846Lymph Nodes2735Enrollment Therapy (%)  Everolimus+exemestane-29Fulvestrant17-Palbociclib+letrozole-16Palbociclib+fulvestrant-12Tamoxifen11-Exemestane6-Letrozole3-Anastrozole2-Palbociclib+exemestane-1Everolimus+tamoxifen-0.5Unknown11Start Dose of Targeted Therapy  Everolimus (n=53); 10, 7.5, 5mg (%)-72, 4, 24Palbociclib (n=54); 125, 100mg, unknown (%)-89, 9, 2On-Study Adverse Events ≥15% (all-grade, %)  Fatigue2332Nausea1224Diarrhea1120Cough815Alopecia316Neutropenia017

Conclusions: The majority of patients enrolled (64%) were receiving endocrine-based targeted therapy (CDK4/6 inhibitor or mTOR inhibitor) combinations. ET+TT patients were younger with more visceral disease and liver metastases compared to patients receiving endocrine therapy alone. Real-world starting dose of targeted therapies appears to be lower than the approved full dose for 11% of patients receiving palbociclib and 28% of patients receiving everolimus. Incidence of reported all-grade adverse events appears to be lower than previously reported in randomized trials and may be a consequence of real-world under-reporting of adverse events as well as the heterogeneous nature of the treatment cohorts. There does however appear to be a trend toward increased incidence of adverse events in the ET+TT cohort compared to the ET cohort.

Citation Format: Doyle C, Califaretti N, Dent S, Iqbal N, Mates M, Kulkarni S, Bains P, Glenns V, Perri SR, Chia S. Treat ER+ight Canadian prospective observational study in HR+ advanced breast cancer: 3rd interim 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 P6-18-34.
Abstract A48: Ado-trastuzumab emtansine (T-DM1) controls tumor progression of established HER2-positive breast cancer brain metastases in mice
Authors: Ferraro Gino B. , Askoxylakis Vasileios , Kodack David P. , Badeaux Mark , Fukumura Dai , Engelman Jeffrey A. , Jain Rakesh K.
Published: May 2019

Brain metastases represent a major problem in the treatment of HER2-positive breast cancer due to the poor efficacy of HER2-targeted therapies in the brain microenvironment. The antibody drug conjugate ado-trastuzumab emtansine (T-DM1) has shown efficacy in trastuzumab-resistant systemic breast cancer. We tested the hypothesis that T-DM1 could overcome trastuzumab resistance in murine models of brain metastases.

Methods: We optimized established animal models of HER2-positive breast cancer brain metastases. We treated mice bearing BT474 (intracranial and intracarotid injections) or MDA-MB-361 (intracranial injection) tumors in the CNS with trastuzumab or T-DM1 at equivalent or equipotent doses. Using intravital imaging, molecular techniques and histological analysis we determined tumor growth, mouse survival, cancer cell apoptosis and proliferation, tumor drug distribution, and HER2 signaling.

Results: Treatment with T-DM1 delayed tumor growth in comparison to trastuzumab and control IgG and improved survival. These findings were consistent between HER2-driven and PI3K-driven breast tumors. In BT474 tumors, median survival was 112 days for T-DM1 and 28 days for trastuzumab (p<0.05). Mechanistic studies revealed no difference in HER2 downstream signaling, drug distribution or immune cell enrichment between T-DM1 and trastuzumab treated mice. A significantly increased apoptotic rate was measured for brain metastases treated with the antibody-drug conjugate.

Conclusions: T-DM1 can overcome resistance to trastuzumab therapy in HER2-driven or PI3K-driven breast cancer brain lesions due to the cytotoxicity of the DM1 component. The results of our studies indicate that T-DM1 is effective in the brain microenvironment and will directly inform clinical trials in patients with HER2+ breast cancer brain metastases.

Citation Format: Gino B. Ferraro, Vasileios Askoxylakis, David P. Kodack, Mark Badeaux, Dai Fukumura, Jeffrey A. Engelman, Rakesh K. Jain. Ado-trastuzumab emtansine (T-DM1) controls tumor progression of established HER2-positive breast cancer brain metastases in mice. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A48.
Abstract A49: WAVE3 modulates sensitivity of TNBCs to chemotherapeutics by inhibiting the STAT-HIF-1α-mediated angiogenesis
Authors: Davuluri Gangarao , Schiemann William P. , Plow Edward F. , Sossey-Alaoui Khalid
Published: May 2019

Chemoresistance allows for disease to recur and ultimately causes the death of most breast cancer patients. This scenario is particularly relevant in patients harboring triple-negative breast cancer (TNBC) tumors for which there are no effective FDA-approved drugs. However, a recent study determined that TNBCs can be segregated into 6 genetically distinct subtypes that do in fact exhibit differential rates of pathological complete response (pCR) to standard-of-care chemotherapies. Of these, the mesenchymal and mesenchymal stem-like subtypes of TNBCs exhibit the lowest rates of pCR when treated with standard-of-care chemotherapies. WAVE3 is an actin-cytoskeleton remodeling protein, and recent studies have highlighted a potential role for WAVE3 in promoting tumor progression and metastasis in TNBC. However, whether WAVE3 activity is involved in the development of chemoresistance in TNBCs remains unclear. Here we show that loss of WAVE3 expression resensitizes human TNBC cells to doxorubicin and docetaxel, as measured by increased apoptosis and cell death. We also show that WAVE3 knockdown in the chemotherapy-treated TNBC cells results in inhibition of STAT1 phosphorylation, as well as a significant decrease in expression levels of its downstream effector HIF-1α. Since HIF-1α is a major activator of VEGF-A production, and therefore a stimulator of tumor angiogenesis, loss of HIF-1α in the WAVE3-knockdown cells resulted in the inhibition the chemotherapy-mediated VEGF-A secretion and the downstream activation of angiogenesis, a phenomenon that often accompanies chemoresistance. Our data identify a critical role of WAVE3 in sensitizing TNBC to chemotherapy by inhibiting the STAT1/HIF-1α/VEGF-A signaling axis, and support the possibility that WAVE3 inhibition may be a promising target for TNBC cancer therapy.

Citation Format: Gangarao Davuluri, William P. Schiemann, Edward F. Plow, Khalid Sossey-Alaoui. WAVE3 modulates sensitivity of TNBCs to chemotherapeutics by inhibiting the STAT-HIF-1α-mediated angiogenesis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A49.
Abstract A59: Macrophages orchestrate early dissemination of HER2+ cancer cells
Authors: Linde Nina , Mortha Arthur , Saenger Nicole , Sosa Maria , Tardio Ethan , Fehm Tanja , Karn Thomas , Merad Miriam , Aguirre-Ghiso Julio
Published: May 2019

Metastatic dissemination can already occur during early pre-invasive breast cancer stages. However mechanisms that control early cancer cell dissemination are unclear. Here we show that MMTV-HER2 early cancer lesions contain an invasive subpopulation of HER2+/E-cadherinlo cancer cells that disseminate by recruiting resident CD206+ mammary tissue resident macrophages (MTMs). This occurs months before monocyte-derived macrophages are recruited into advanced tumors. Early HER2+ lesions, but not healthy mammary tissue, produced CCL2 in an NFκB dependent manner and recruited intra-ductal MTMs, that secreted Wnt1 and thereby induced an epithelial to mesenchymal transition (EMT) in the early HER2+ cancer cells. Depletion of MTMs before overt tumors appeared prevented early cancer cells from undergoing an EMT and drastically reduced early dissemination. Surprisingly macrophage depleting therapy in MMTV-Her2 only during pre-malignant stages reduced alveolar metastases, even when mice went through invasive tumor stages and macrophages had repopulated the overt tumor tissue. Importantly, humans with DCIS lesions that contained macrophage+/E-Cadherinlo microenvironments frequently had disseminated cancer cell (DCCs) in the bone marrow. Taken together, we reveal that resident MTMs can promote early dissemination explaining how early cancer spread might proceed in breast cancer patients. We also propose that eDCCs play a long-term causal role in metastasis development.

Citation Format: Nina Linde, Arthur Mortha, Nicole Saenger, Maria Sosa, Ethan Tardio, Tanja Fehm, Thomas Karn, Miriam Merad, Julio Aguirre-Ghiso. Macrophages orchestrate early dissemination of HER2+ cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A59.
Abstract A63: IFNAR1 downregulation during melanoma progression upregulates αv expression and promotes metastasis
Authors: Ortiz Angelica , Katlinskaya Yuliya V. , Katlinski Kanstantsin V. , Fuchs Serge Y.
Published: May 2019

The anti-metastatic effects of type 1 interferon (IFN1) prompted its use for adjuvant therapy in malignant melanoma patients at high risk for developing metastasis. While IFN1 adjuvant therapy continues to be the preferred treatment, many patients fail to elicit response to IFN1 treatment and progress to develop distal metastases often resulting in a lethal outcome. We observed downregulation of the IFNAR1 chain of the IFN1 receptor and suppression of IFN1 signaling in genetically engineered mouse melanomas driven by melanocyte-specific activation of Braf and inactivation of Pten. Induction of melanoma in animals expressing IFNAR1 that is deficient in ubiquitination and degradation led to a delayed onset of the disease and decreased number of local metastases. Remarkably, no distant metastases were found in these mice despite substantial primary tumor burden. Gene set enrichment analysis demonstrated a dramatic loss of the αv integrin pathway signature in mice harboring stabilized IFNAR1. Conversely, melanomas induced in Ifnar1 knockout mice yielded transplantable cell lines that displayed high levels of αv expression. Restoring IFNAR1 expression in these cells led to the loss of αv expression. We discuss the role of these mechanisms in melanoma metastasis and refractoriness to IFN1-based therapy.

Citation Format: Angelica Ortiz, Yuliya V. Katlinskaya, Kanstantsin V. Katlinski, Serge Y. Fuchs. IFNAR1 downregulation during melanoma progression upregulates αv expression and promotes metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A63.
Abstract B07: Gain of function activities of p53R245W in a conditional knock-in mouse model
Authors: Xiong Shunbin , Zhang Yun , Lozano Guillermina
Published: May 2019

Missense mutations of the p53 tumor suppressor gene are present in more than 50% of human tumors. Emerging evidence suggests that p53 missense mutations in human cancer patients are associated with the poor prognosis and drug resistance due to their gain-of-function (GOF) properties, rather than just the loss of normal p53 function. Interestingly, these missense mutations have been shown to contribute to tumor progression by different mechanisms: interactions with Smad and SREBPs, modulation of EGFR/integrin signaling, and inhibition of p63 and p73 tumor suppressors. Combined, these studies suggest that the GOF of p53 missense mutations may be dependent on cell contexts and mutation types. Of particular interest, the p53R248W mutation is one of the most frequent missense mutation among human cancer patients; yet to date a mouse model that faithfully mimics this mutation does not exist. Additionally, the majority of human cancers evolve from somatic inactivation of p53 and current mouse models do not mimic somatic mutation of p53. Thus, we generated a conditional p53WMR245/+ knock-in mouse model, which normally expresses wild type p53, but produces p53R245W by Cre-mediated deletion of wild type p53 sequences. Germ line mutation of p53R245W/+ can rescue the early embryonic lethality of Mdm2 and Mdm4 null alleles like p53 null. Preliminary analyses of p53R245W/+ cohorts indicate differences in tumor spectrum in comparison to p53+/- and p53R172H/+ mice. Somatic mutation of p53R245W has also been performed to examine germ line versus somatic differences in tumor development. This study will help us understand the in vivo contributions of different p53 missense mutations to tumorigenesis, as well as the genetic alterations that occur during tumor evolution initiated by both germ line and somatic p53 mutations.

Citation Format: Shunbin Xiong, Yun Zhang, Guillermina Lozano. Gain of function activities of p53R245W in a conditional knock-in mouse model. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B07.
Abstract B30: Rnaseh2c is a candidate metastasis susceptibility gene in breast cancer
Authors: Deasy Sarah , Hunter Kent
Published: May 2019

Breast cancer is a leading cause of cancer-related female deaths in the United States, the majority of which are due to distant metastases. Elucidating novel genes that drive metastasis is critical to improving patient outcome. Our laboratory has extensively shown that germline variants impact an individual's susceptibility for metastasis, and we have used this to identify novel metastasis modifier genes. Here we applied a mouse model of spontaneous metastasis to a mouse breeding scheme to screen for strain-specific haplotypes associated with metastatic phenotype. Additional filtering of the haplotype-containing genes was performed for those that were highly expressed in tumors. This screen identified Rnaseh2c, a scaffolding subunit of the Ribonuclease H2 complex which degrades RNA from DNA:RNA heteroduplexes such as those generated during replication and transcription, thus helping maintain genomic stability. Though mutations in RNASEH2C are known to cause the neurological autoinflammatory disorder Aicardi-Goutières Syndrome (AGS), it has not previously been linked to cancer. Given the known pathology of AGS, we hypothesize that differential expression of Rnaseh2c in tumor cells alters tumor progression and metastasis potentially via interaction with the immune system. We directly assessed the effect of tumor cell Rnaseh2c expression on metastasis using in vivo metastasis assays. We implanted into the mammary fat pad tumor cells expressing shRNAs that reduced Rnaseh2c expression and observed significantly fewer pulmonary metastases and reduced tumor burden. To complement this approach, we performed the same metastasis assay with cells overexpressing exogenous Rnaseh2c. In agreement with our initial result, overexpression generated significantly more metastases without affecting primary tumor size, confirming Rnaseh2c as a metastasis modifier. The results thus far validate our approach of employing germline variation in mice to identify novel metastasis modifier genes. Current and future work will focus on elucidating the mechanism by which Rnaseh2c expression impacts metastasis. Specifically, we will determine where Rnaseh2c functions in the metastatic cascade, whether modulated expression disrupts Rnase H2 complex formation, and whether the immune system is involved in mediating this gene's effect on metastasis. Elucidating the mechanism by which this gene acts can contribute to both the development of novel metastasis biomarkers as well as potential therapeutic targets.

Citation Format: Sarah Deasy, Kent Hunter. Rnaseh2c is a candidate metastasis susceptibility gene in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B30.
Abstract B33: Beyond apoptosis, Bcl-xL in metastasis
Authors: Choi Soyoung , Chen Zhengming , Tang Laura , Fang Yuanzhang , Li Yi , Jiang Xuejun , Du Yi-Chieh Nancy
Published: May 2019

Bcl-xL, a negative regulator of mitochondria-mediated apoptosis, is frequently overexpressed in cancer to promote survival. Bcl-xL can also promote migration and/or metastasis. However, it is unclear whether this metastatic function is mediated via – or independent of – its anti-apoptotic activity and its residence at mitochondria. Here, we show that Bcl-xL promotes migration of cells defective in mitochondria-mediated apoptosis. Importantly, Bcl-xL mutants lacking anti-apoptotic activity still induce epithelial-mesenchymal transition (EMT), upregulate TGFβ, and increase metastasis of pancreatic neuroendocrine tumor (panNET) cells. In the RIP-Tag; RIP-tva mouse model, infection of pancreatic lesions with avian retroviruses carrying such Bcl-xL mutants promotes metastasis as potently as wild-type Bcl-xL does. Furthermore, engineered Bcl-xL targeted to the nucleus, but not mitochondria or outside of nucleus, promotes EMT and alters EMT-associated factors. In addition, nuclear Bcl-xL can be found in human metastatic panNET samples. Taken together, these data demonstrate that the metastatic function of Bcl-xL is independent of its anti-apoptotic activity and its residence at mitochondria.

Citation Format: Soyoung Choi, Zhengming Chen, Laura Tang, Yuanzhang Fang, Yi Li, Xuejun Jiang, Yi-Chieh Nancy Du. Beyond apoptosis, Bcl-xL in metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B33.
Abstract B34: CDKL2 promotes epithelial-mesenchymal transition and breast cancer progression
Authors: Li Linna , Hulsurkar Mohit , Amato Robert , Chang Jeffrey , Du Guangwei , Li Wenliang
Published: May 2019

The epithelial-mesenchymal transition (EMT) confers mesenchymal properties on epithelial cells and has been closely associated with the acquisition of aggressive traits by epithelial cancer cells. To identify novel regulators of EMT, we carried out cDNA screens that covered 500 human kinases. Subsequent characterization of candidate kinases led us to uncover cyclin-dependent kinase-like 2 (CDKL2) as a novel potent promoter for EMT and breast cancer progression. CDKL2-expressing human mammary gland epithelial cells displayed enhanced mesenchymal traits and stem cell-like phenotypes, which was acquired through activating a ZEB1/E-cadherin/beta-catenin positive feedback loop and regulating CD44 mRNA alternative splicing to promote conversion of CD24-high cells to CD44-high cells. Furthermore, CDKL2 enhanced primary tumor formation and metastasis in a breast cancer xenograft model. Notably, CDKL2 is expressed significantly higher in mesenchymal human breast cancer cell lines than in epithelial lines, and its over-expression/amplification in human breast cancers is associated with shorter disease-free survival. Taken together, our study uncovered a major role for CDKL2 in promoting EMT and breast cancer progression.

Citation Format: Linna Li, Mohit Hulsurkar, Robert Amato, Jeffrey Chang, Guangwei Du, Wenliang Li. CDKL2 promotes epithelial-mesenchymal transition and breast cancer progression. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B34.
Abstract B36: Rab25 aggravates cancer cell invasion through Snail expression
Authors: Jeong Bo Young , Cho Kyung Hwa , Kim Seung Hwa , Kim Yu Na , Park Chang Gyo , Lee Hoi Young
Published: May 2019

Background: Rab25 is a member of the Rab11 subfamily and exclusively expressed in epithelial cells. As a small GTP-binding protein, Rab25 has been known to mediate recycling of proteins from the endosome to the plasma membrane. Cancer metastasis is multi-step events including epithelial-to-mesenchymal transition (EMT). Various transcription factors mediate EMT through downregulation of E-cadherin. In the present study, we investigate whether Rab25 induces EMT transcription factors, thereby increasing cancer invasiveness.

Methods: Immunoblotting, quantitative RT-PCR and immunofluorescence assay were used to examine the expression of Rab25 and EMT factors. siRNAs of Rab25 and Snail were transfected to determine their role in Rab25-induced cancer cell EMT and invasiveness. Transwell invasion assay were used to determine cancer cell invasiveness.

Results: Ectopic expression of Rab25 marked reduced E-cadherin expression, while Snail expression was upregulated. In addition, Rab25 significantly aggravated cancer cell invasiveness. However, silencing Snail expression by utilizing specific siRNA significantly attenuated cancer cell invasion. In addition, Rab25 induced phosphorylation of Akt and GSK-3beta. However, pharmacological inhibition of Akt and GSK-3beta marked attenuated Rab25-induced Snail expression. Further, we observed that a beta1integrin located upstream of an Akt/GSK-3beta signaling is important for Rab25-induced Snail expression and cancer cell invasion.

Conclusion: Our results show for the first time that Snail mediates Rab25-induced cancer cell EMT and invasiveness through a beta1 integrin /Akt/GSK-3beta signaling cascade, providing novel biomarkers, and potential therapeutic targets for deadly cancers.

Citation Format: Bo Young Jeong, Kyung Hwa Cho, Seung Hwa Kim, Yu Na Kim, Chang Gyo Park, Hoi Young Lee. Rab25 aggravates cancer cell invasion through Snail expression. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B36.
Abstract B51: Extracellular matrix control of metastasis and dormancy
Authors: Barney Lauren E. , Gilman Ari , Mercurio Arthur , Peyton Shelly R.
Published: May 2019

This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR14) of the Conference Proceedings.

Citation Format: Lauren E. Barney, Ari Gilman, Arthur Mercurio, Shelly R. Peyton. Extracellular matrix control of metastasis and dormancy. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B51.
Abstract B58: CELF1 is a central node in post-transcriptional regulatory programs underlying EMT and metastasis in breast epithelial cells
Authors: Chaudhury Arindam , Kongchan Natee , Fachini Joseph M. , Simon Lukas M. , Wang Tao , Mao Sufeng , Rosen Daniel G. , Ittmann Michael M. , Hilsenbeck Susan G. , Shaw Chad A. , Neilson Joel R.
Published: May 2019

The importance of translational regulation in tumorigenesis and metastasis is increasingly appreciated. We have leveraged polyribosomal profiling to prospectively and functionally define translational regulatory programs underlying the epithelial to mesenchymal transition (EMT), one of the early manifestations of metastasis, in breast epithelial cells. Our approach identified scores of mRNAs both enriched and depleted from polyribosomal fractions in mesenchymal cells as compared to their epithelial counterparts. Computational analysis of the 3′ untranslated regions (UTRs) of mRNAs enriched in polysomal fractions derived from the mesenchymal state revealed enrichment of a distinct GU-rich cis-element within these mRNA transcripts. Strikingly, while relative representation of these GU-rich-containing transcripts at the level of bulk mRNA were generally decreased in mesenchymal cells, the protein encoded by each of these mRNAs was dramatically increased. 3′ UTRs from affected transcripts conferred similar regulation upon a fluorescent reporter gene dependent upon the presence of the GU-rich element within the 3′ UTR sequence. Several of the translationally upregulated transcripts were necessary and/or sufficient for the EMT program. We next identified the CELF1 protein as a common regulator of these mRNA transcripts, demonstrating direct binding of the CELF1 protein to affected transcripts dependent upon the presence of the GU-rich element within their 3′ UTRs. CELF1 was itself necessary and sufficient for EMT in several distinct in vitro models as well as for metastatic colonization in vivo. Analysis of publicly available transcriptomic data revealed no increase in the relative expression of CELF1's regulatory targets or CELF1 itself in human breast cancer. We demonstrate that the CELF1 gene product is itself post-translationally regulated during EMT, and that CELF1 protein, but not mRNA, is significantly overexpressed in human breast cancer tissues and correlates with disease progression. Cumulatively, our data present a distinctive model of gene regulation, invisible to traditional transcriptional profiling, in which the CELF1 protein serves as a central node controlling translational activation of the EMT program and ultimately tumor metastasis in human breast cancer.

Citation Format: Arindam Chaudhury, Natee Kongchan, Joseph M. Fachini, Lukas M. Simon, Tao Wang, Sufeng Mao, Daniel G. Rosen, Michael M. Ittmann, Susan G. Hilsenbeck, Chad A. Shaw, Joel R. Neilson. CELF1 is a central node in post-transcriptional regulatory programs underlying EMT and metastasis in breast epithelial cells. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B58.
Abstract B59: Control of invasion by PKC theta in triple-negative breast cancer
Authors: Chadelle Lucie , Cadamuro Valérie , Liu Jiaying , Wang Xiaobo , Belguise Karine
Published: May 2019

Triple-negative breast cancers (TNBC: negative for oestrogen-receptor, progesterone-receptor and human-epidermal-growth-factor receptor 2 [HER2]) account for 15-20% of breast cancers and are characterized by an extremely aggressive phenotype. Currently, there is no efficient targeted therapy that can prevent the metastatic dissemination of TNBC. The serine threonine kinase PKCθ has recently been identified as a potential new marker of TNBC and as a strong inducer of cancer invasion. However, how PKCθ controls tumour invasion in TNBC is still unclear. Here our results suggest that PKCθ can promote invasion by activating the focal adhesion kinase (FAK) signalling that regulates the cycle of focal contact formation and disassembly. As a consequence of this activation, PKCθ enhances the dynamic of adhesion turnover, Rho GTPases activity and protrusions formation. We also have unravelled the molecular mechanisms by which PKCθ controls FAK: PKCθ interacts with and phosphorylates FAK thus leading to its opening and activation. We believe that the identified phosphorylation sites are implicated in the PKCθ controlled invasion. In the long term, this study could help develop new targeted therapy for TNBC such as PKCθ specific inhibitors that would limit metastasis formation.

Citation Format: Lucie Chadelle, Valérie Cadamuro, Jiaying Liu, Xiaobo Wang, Karine Belguise. Control of invasion by PKC theta in triple-negative breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B59.
Abstract IA20: Quantifying patterns of tumor evolution
Authors: Markowetz Florian
Published: May 2019

Cancer has long been understood as a somatic evolutionary process, but many details of tumor progression remain elusive. Here, I will talk about computational methods to infer evolutionary pathways leading to tumor heterogeneity. I will start by discussing how to quantify intra-patient heterogeneity by rigorous analysis of copy-number profiles from multiple patient samples. Using a study in ovarian cancer I will describe how summary statistics of phylogenetic quantification of genetic heterogeneity can predict patient survival. Then, I will present a probabilistic framework to reconstruct intra-tumor evolution from data obtained by bulk bisulfite sequencing of mixed tumor samples or single cell genomes. Our approach jointly estimates the number and composition of clones in the sample as well as the most likely tree connecting them. I will finish by describing ongoing work to reconstruct patterns of clonal evolution from single cell sequencing data.

Citation Format: Florian Markowetz. Quantifying patterns of tumor evolution. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr IA20.
Abstract IA24: The role of CCL18 signaling in breast tumor associated macrophages promoting cancer progression
Authors: Song Erwei
Published: May 2019

Tumor-associated macrophages (TAMs) play critical roles in cancer progression. We focus on dissecting their underlying molecular mechanisms by applying human sample-based approaches, which include humanized mice, clinical samples and online clinical databases. Our data showed that CCL18, one of the most abundantly produced cytokines from human breast TAMs, is closely associated with advanced histopathological grading, triple negative breast cancer subtype, lymphovascular invasion, distant metastasis and poor prognosis of breast cancer patients. Mechanistic studies revealed that CCL18 induces epithelial-mesenchymal transition (EMT) and inflammatory cytokine secretion of tumor cells by activating NFkB pathway. Among the cytokines induced by CCL18, GM-CSF released from tumor cells undergone EMT in turn enhances the CCL18 production from TAMs and forms a positive feedback loop, which is essential to breast cancer metastasis, especially in the triple negative subtype. In addition, our recent study demonstrated that CCL18 could also mediate the activation and functions of other stromal cells in tumor microenvironment, leading to angiogenesis, recruitment of naïve T cells and activation of a special subset of chemoresistance-inducing fibroblasts. Previously, the receptor of CCL18 remained unknown. By using immunoprecipitation and mass spectra of the membrane extracts, cell-free isotope binding assays, [Ca2+]I mobilization and cAMP assays, we identified PITPNM3 as a functional receptor for CCL18. RNAi silencing of PITPNM3 in either cancer cells or stromal cells significantly inhibited the tumor progression in vivo. In conclusion, we define CCL18 from TAMs as the axis of a novel inflammatory signaling network in tumor microenvironment and imply the potential clinical application by targeting its receptor.

Citation Format: Erwei Song. The role of CCL18 signaling in breast tumor associated macrophages promoting cancer progression. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr IA24.