bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract S2-06: Extracellular matrix stiffness modulates tissue inflammation to promote breast tumor aggression
Authors: Acerbi I , Hwang S , Munson J , Au A , Zheng S , Yu H , Mouw J , Lakins J , Swartz M , Shi Q , Liphardt J , Ruffell B , Coussen LM , Yunn-Yi C , Weaver VM
Published: August 2014

Tumor progression is influenced by the dynamic interplay between the genetically-modified epithelium and the associated microenvironment. We previously showed that the extra-cellular matrix (ECM) progressively stiffens as mammary tumors evolve, and that stiffening the ECM promotes malignant transformation while inhibiting ECM stiffening reduces tumor progression (Levental et al., 2009; reviewed in Butcher et al., 2009). Yet breast cancers also exhibit elevated influx of inflammatory cells and tissue inflammation promotes tumor progression by fostering angiogenesis and enhancing tumor cell growth and motility (Ruffell et al., 2011). Tumor-associated macrophages additionally stimulate stromal fibroblasts, implying that tissue inflammation could promote malignancy by stiffening the ECM. To address this possibility, we explored the relationship between ECM tension and macrophages in human breast cancer and during mammary tumor development in transgenic mice. Using fresh and archived tissue samples, we quantified a progressive increase in ECM remodeling and stiffening as human breast tumors and mouse mammary cancers developed. We found that the ECM associated with triple negative breast cancers was almost twice as stiff as the ECM adjacent to ER+/PR+ tumors and that ECM stiffness correlated significantly with increased numbers of infiltrating activated macrophages. Consistently, we established a positive correlation between tumor progression, elevated mechanosignaling, ECM stiffness and tissue inflammation in both human and mouse tissue. However surprisingly, when macrophages were depleted from the mammary glands of MMTV-PyMT tumors, ECM tension did not change. Instead we found that inhibiting lysyl oxidase activity to decrease collagen cross-linking and ECM stiffness reduced the activation state of the macrophages within the mammary glands of 14-week old mice. Consistently, in vitro studies showed that ECM tension potentiates the expression of pro-inflammatory chemokines and increases levels of phosphoStat3 and that ECM tension directly modifies macrophage polarity. These findings suggest that ECM tension may promote malignancy either by directly regulating macrophage activity or indirectly through enhancing expression of pro-inflammatory chemokines. Further studies are now underway to explore these findings and to clarify their impact on tumor progression and response to therapy.

Acknowledgements: supported by W81XWH-05-1-0330 and R01 CA138818-01A1 to VMW, 1U01 ES019458-01 to VMW and ZW, and P50 CA 58207 to JG, VW, SH and LC, U54CA143836-01 to JL and VW, and Susan G. Komen for the Cure PSF12230246 to IA.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S2-06.
Abstract S5-05: Postneoadjuvant treatment with zoledronate in patients with tumor residuals after anthracyclines-taxane-based chemotherapy for primary breast cancer – The phase III NATAN study (GBG 36/ABCSG XX)
Authors: von Minckwitz G , Rezai M , Eidtmann H , Tesch H , Huober J , Gerber B , Zahn DM , Costa S , Gnant M , Blohmer JU , Denkert C , Hanusch C , Jackisch C , Kümmel S , Fasching PA , Schneeweiss A , Paepke S , Untch M , Nekljudova V , Mehta K , Loibl S
Published: August 2014

Background: Patients with residual disease after neoadjuvant chemotherapy (NACT) are considered to have chemoresistant breast cancer. Adjuvant treatment with bisphosphonates is considered to reduce the relapse risk predominantly in estrogen-deprivated patients.

Methods: Patients who had invasive tumor residuals (ypT1-4 or ypN+) after a minimum of 4 cycles of anthracycline-taxane-containing NACT were eligible to the NATAN study. Patients were randomized within 3 years after surgery to receive zoledronate 4 mg i.v. (plus 1000 mg Ca2+ and 880 I.U. vitamin D daily) for 5 years vs. observation. Zoledronate was given q 4 weeks for the first 6 months, q 3 months the following 2 years, and q 6 months for the last 2.5 years. Patients with hormone receptor (HR)-positive disease received letrozole for 5 years if postmenopausal, or tamoxifen, if premenopausal. Adjuvant trastuzumab for HER2-positive disease was allowed since an amendment in 2007. Stratification factors were HR, time since surgery, age, and center. Primary objective was event-free survival (EFS). 654 patients and 316 events were required to observe an increase of 5yr EFS from 58% to 67.2% (hazard ratio 0.73). Secondary objectives were to determine overall survival, EFS with respect to the interval between surgery and randomization, bone-metastasis-free-survival, toxicity of and compliance to zoledronate, the predictive value of breast tumor response to NACT on the effect of postoperative treatment and the prognostic impact of chemotherapy induced amenorrhea in premenopausal patients. An interim analysis for high efficacy at 158 observed events was planned in the protocol; in agreement with study IDMC a Bayesian analysis for futility with futility boundary of 15% will be performed at the same time.

Results: Between 2/2005 and 5/2009 693 patients were enrolled. Time between surgery and randomization was <4 months in 48.4%, 4-12 months in 34.5%, and 13-36 months in 17.1% of patients. The median age was 50.9 yrs (range 33.7-88.2), 72.3% of patients were postmenopausal. 82% had HR-positive and 19% HER2-positive disease. During a median follow up of 48 months 154 events were observed so far.

Conclusion: This is the first post-neoadjuvant phase III study. Analysis of the primary endpoint will be presented in case the IDMC will release of the results of the futility analysis.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S5-05.
Abstract A06: Reducing decision errors in the paired comparison of the diagnostic accuracy of continuous screening tests.
Authors: Ringham Brandy M. , Alonzo Todd A. , Brinton John T. , Muller Keith E. , Glueck Deborah H.
Published: August 2014

Scientists often use a paired comparison of the areas under the receiver operating characteristic curves to decide which continuous cancer screening test has the best diagnostic accuracy. In the paired design, all participants are screened with both tests. Participants with unremarkable screening results enter a follow-up period. Participants with suspicious screening results and those who show evidence of disease during follow-up receive the gold standard test. The remaining participants are classified as non-cases, even though some may have occult disease. The standard analysis includes all study participants in the analysis, which can create bias in the estimates of diagnostic accuracy. If the bias affects the area under the curve for one screening test more than the other screening test, scientists may make the wrong decision as to which screening test has better diagnostic accuracy. We propose a weighted maximum likelihood bias-correction method to reduce decision errors. The amount of bias in the study and the performance of the bias correction method depend on characteristics of the screening tests and the disease, and on the percentage of study participants who receive the gold standard test. In order to determine if bias correction is needed for a specific screening trial, we recommend the investigator conduct a simulation study using our software. We demonstrate the proposed method with an application to a hypothetical oral cancer screening study.

Citation Format: Brandy M. Ringham, Todd A. Alonzo, John T. Brinton, Keith E. Muller, Deborah H. Glueck. Reducing decision errors in the paired comparison of the diagnostic accuracy of continuous screening tests. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr A06.
Abstract A41: Dasatinib regulation of N-glycans induce anticancer activity in hematological and solid tumor malignancies.
Authors: Saunders Mary R. , Ruhaak L. Renee , Williams Cynthia , Olivos David J. , Stroble Carol , An Hyun Joo , Miyamoto Suzanne , Lebrilla Carlito B. , Lam Kit S.
Published: August 2014

Glycans are carbohydrates covalently bound to proteins or lipids. Changes in their content and structure, particularly in asparagine-linked oligosaccharides, contribute to a variety of events during malignant transformation. These include the loss of cell-matrix adhesion, migration, invasion, metastasis, and evasion of cell death. High mannose glycans are not commonly present on the surfaces of normal mammalian cells or in serum, yet they play important roles in cancer cell biology. Therefore, modulation of glycan expression with drugs offers a promising therapeutic approach for various hematological and solid tumor cancers, several of which disproportionally afflict minority populations. Dasatinib, a dual inhibitor of Src and Abl tyrosine kinase, is used to investigate in vitro anti-cancer activity in several cancer cell lines: Jurkat lymphoblastic leukemia, Raji lymphoblastic lymphoma, SiHa cervical cancer, H1650 non small cell lung cancer, PC3N prostate cancer, SKOV3 ovarian cancer, and MCF7 breast cancer. To address how the carbohydrate moieties of the cancer cells are affected during treatment, the glycan profiles from treated cells are compared to non-treated cells and normal controls and analyzed by matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS). PCR arrays are used to profile glycosylation enzyme gene expression changes due to dasatinib-induced cytotoxicity. Protein expression arrays are used to investigate Src and Abl receptor tyrosine kinase signaling cascades. The results presented here demonstrate new evidence of glycosylation expression changes and the related mechanisms of their anticancer activity. Regulation of glycosylation is a promising therapeutic strategy for inducing anticancer activity through cell arrest, apoptosis, and autophagy.

Citation Format: Mary R. Saunders, L. Renee Ruhaak, Cynthia Williams, David J. Olivos, Carol Stroble, Hyun Joo An, Suzanne Miyamoto, Carlito B. Lebrilla, Kit S. Lam. Dasatinib regulation of N-glycans induce anticancer activity in hematological and solid tumor malignancies. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr A41.
Abstract A71: Smoking and breast cancer survival among New Mexican Hispanic and non-Hispanic white women.
Authors: Baumgartner Kathy B. , Pinkston Christina , Connor Avonne , Denkhoff Stephanie , Yang Dongyan , Baumgartner Richard N.
Published: August 2014

The association of smoking with breast cancer mortality is not well established. Results from the few studies to date are mixed. Data for ethnic minorities are sparse. The current study examined the association of active cigarette smoking with breast cancer and non-breast cancer mortality in a pooled sample of 1,368 New Mexico Hispanic women (n=556) and non-Hispanic white (NHW) women (n=812) diagnosed with a first primary invasive breast cancer from two case-control studies: the New Mexico Women's Health Study (NMWHS: 1992-1994) and the 4-Corner's Breast Cancer Study (4-CBCS: 1999-2004). The cases were ascertained by the New Mexico Tumor Registry. Baseline data were collected for smoking exposure and other relevant covariates (age, study, alcohol intake, body mass index, menopausal status, family history, parity, energy intake and expenditure). The National Death Index was used to determine vital status through December 31, 2008. A total of 312 deaths occurred over an average of 9.2 years of follow-up (NMWHS, 12.4; 4-CBCS, 7.2); 188 were breast cancer deaths. The prevalence of current and former smoking was 13% and 25% in Hispanic women compared to 16% and 32% in NHW women. Thirty-three percent of NHW women smoked for more than 13 pack-years versus 16% of Hispanic women. Hazard ratios were calculated using Cox Proportional analysis adjusting for the covariates. Cigarette smoking status (former, current) and pack-years were not associated with breast cancer mortality in Hispanic women. However, there was a non-significant positive association in NHW women who smoked (current: HR, 1.42, 95% CI 0.83-2.41; pack-years >13: HR, 1.42; 95% CI 0.90-2.24). In contrast, there were significant positive associations with non-breast cancer mortality in H women (pack-years >13: HR, 2.95; 95% CI 1.52-5.75) and NHW women (pack-years >13: HR, 2.08; 95% CI 1.25-3.45). These results do not support an association of smoking with breast cancer mortality, particularly in Hispanic women. However, smoking is significantly associated with non-breast cancer mortality in women diagnosed with breast cancer.

Citation Format: Kathy B. Baumgartner, Christina Pinkston, Avonne Connor, Stephanie Denkhoff, Dongyan Yang, Richard N. Baumgartner. Smoking and breast cancer survival among New Mexican Hispanic and non-Hispanic white women. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr A71.
Abstract B03: Effectiveness of lay health worker outreach in reducing colorectal cancer screening disparities in Vietnamese Americans.
Authors: Nguyen Bang H. , Stewart Susan L. , Nguyen Tung T. , McPhee Stephen J. , Tran Mai T. , Pham Alene L. , Bui-Tong Ngoc
Published: August 2014

Purposes: Vietnamese Americans have lower colorectal cancer (CRC) screening rates than non-Hispanic whites. The purposes of this study were to increase CRC screening in Vietnamese Americans and thereby to reduce CRC screening disparities in Vietnamese Americans.

Procedures: Using a Community-Based Participatory Research (CBPR) approach and a cluster randomized controlled design, Lay Health Workers (LHWs) recruited participants aged 50-74 years for an intervention (I) (n=316) or control arm (C) (n=311). At pre-intervention all participants self-reported not having been screened for CRC as an eligibility criterion. LHWs delivered 2 educational sessions about CRC screening to the intervention arm participants; the control arm attended sessions about healthy eating and physical activities. Effectiveness was measured using pre-intervention (Pre) and post-intervention (Post) surveys. Outcomes were: 1) self-reported behavior: having ever had CRC screening; 2) recognition: having ever heard of colon cancer; 3) perceived susceptibility: worrying about getting colon cancer and having ever thought might get colon cancer; 4) beliefs: believing colon cancer can be cured if founded early; and 5) knowledge: having heard of colon polyps and knowing the recommended age to begin CRC screening. Generalized estimating equations (GEE) models were used to test the effectiveness of the intervention while accounting for correlated data.

Results: The intervention group was significantly more likely than the control group to report having had CRC screening at post-test (56% v 19%, p<.0001). In addition, the intervention group had significantly greater increases in the proportion who had heard of colon cancer, believed that colon cancer can be cured if found early, heard of colon polyps, and knew the age to begin CRC screening. The two groups had similar increases in the proportion of participants who ever thought they might get colon cancer, and controls had a greater increase in the proportion who worried about getting colon cancer.

Conclusions: LHW outreach was effective in increasing CRC screening among Vietnamese Americans. The intervention also increased recognition, beliefs in the efficacy of screening, and knowledge of CRC and CRC screening. Self-reported behavior should be validated using objective measures.

Citation Format: Bang H. Nguyen, Susan L. Stewart, Tung T. Nguyen, Stephen J. McPhee, Mai T. Tran, Alene L. Pham, Ngoc Bui-Tong. Effectiveness of lay health worker outreach in reducing colorectal cancer screening disparities in Vietnamese Americans. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr B03.
Abstract B21: The moderating effect of acculturation on gender roles and cancer screening variables among Vietnamese American women.
Authors: Nguyen Anh Bao , Clark Trenette T. , Belgrave Faye Z.
Published: August 2014

Vietnamese women are less likely to undergo cancer screening in comparison to women from other ethnic and minority populations. These health disparities suggest the need to uncover both access/structural barriers as well as cultural barriers to cancer screening for Vietnamese women. The aim of the present study was to examine the influence of demographic variables and the interplay between gender roles and acculturation on breast and cervical cancer screening outcomes among Vietnamese women. A convenience sample of 100 Vietnamese women were recruited from two faith-based institutions for a larger cancer-screening intervention. All participants completed measures on demographic variables, measures of gender roles and acculturation, and cancer screening variables. Results indicated that traditional masculine gender roles were associated with increased self-efficacy for breast and cervical cancer screening. Higher levels of acculturation were associated with higher probability of having had a Pap test. Lastly, acculturation moderated the relationship between traditional female gender roles and cancer screening variables. For highly acculturated women, higher levels of feminine gender roles predicted higher probability of having had a previous CBE and higher levels of self-efficacy for cervical cancer screening, while the opposite was true for lower acculturated women. The findings provide evidence for the interplay between gender and cultural identities and how they may impact Vietnamese women's health outcomes. Programming and intervention strategies need to recognize intra-group differences within ethnic minority populations.

Citation Format: Anh Bao Nguyen, Trenette T. Clark, Faye Z. Belgrave. The moderating effect of acculturation on gender roles and cancer screening variables among Vietnamese American women. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr B21.
Abstract B31: Expression of Wnt3 activates Wnt/β-catenin pathway and promotes EMT-like phenotype in trastuzumab resistant HER2-overexpressing breast cancer cells.
Authors: Wu Yanyuan , Ginther Charles , Kim Juri , Mosher Nicole , Chung Seyung , Slamon Dennis , Vadgama Jaydutt V.
Published: August 2014

To understand the mechanisms leading to trastuzumab resistance in HER2-overexpressing breast tumors we created trastuzumab insensitive cell lines (SKBR3/100-8 and BT474/100-2). The cell lines maintain HER2 receptor overexpression, and show increase in EGFR. Upon trastuzumab treatment, SKBR3/100-8 and BT474/100-2 cell lines displayed increased growth rate and invasiveness. The trastuzumab resistance in SKBR3/100-8 and BT474/100-2 was accompanied with activation of the Wnt/β-catenin signaling pathway. Further investigation found that Wnt3 overexpression played a key role toward the development of trastuzumab resistance. The expression of Wnt3 in trastuzumab resistant cells increased nuclear expression of β-catenin and transactivated expression of EGFR. The increased Wnt3 in the trastuzumab resistant cells also promoted a parental EMT-like transition (epithelial to mesenchymal transition), increased N-cadherin, Twist, SLUG and decreased E-cadherin. Knockdown Wnt3 by siRNA restored cytoplasmic expression of β-catenin, and decreased EGFR expression in trastuzumab resistant cells. Furthermore the EMT markers were decreased, E-cadherin was increased and the cell invasiveness was inhibited in response to the Wnt3 down-regulation. Conversely, SKBR3 cells which had been stably transfected with full-length Wnt3 exhibited EMT-like transition. The Wnt3 transfectants, SKBR3/Wnt3-7 and SKBR3/Wnt3-9, showed significant decrease in E-cadherin and increase in N-cadherin, Twist and SLUG. The cells were less sensitive to trastuzumab compared to parental SKBR3 and vector transfected cells. In summary, our data suggests that Wnt3 overexpression activates Wnt/β-catenin signaling pathway that leads to transactivation of EGFR and promotes EMT-like transition. This could be an important mechanism leading to trastuzumab resistance in HER2 overexpressing breast cancer cells.

Citation Format: Yanyuan Wu, Charles Ginther, Juri Kim, Nicole Mosher, Seyung Chung, Dennis Slamon, Jaydutt V. Vadgama. Expression of Wnt3 activates Wnt/β-catenin pathway and promotes EMT-like phenotype in trastuzumab resistant HER2-overexpressing breast cancer cells. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr B31.
Abstract B38: Profiling miR-152 expression in African American prostate cancer cell lines.
Authors: Theodore Shaniece Crystal , Davis Melissa , Jhong Rhim , Turner Timothy , Yates Clayton
Published: August 2014

Purpose: African American men have almost twice the incidence and death rates related to prostate cancer compared to Caucasian men. Several studies have suggested that some of these differences may be attributed to the elevated expression of different genes. Recently, a new class of genetic regulators has emerged known as microRNAs. Many reports have found microRNAs to be implicated in cell growth, cell differentiation and the onset of many diseases including prostate cancer. To date, there are only three commercially available African American prostate cancer cell line models. We were able to establish five African American prostate cell lines, representing each stage of prostate cancer progression. With the help of these models, we sought out to investigate the difference of microRNA expression in African American and Caucasian prostate cancer.

Methods: We analyzed the expression of over 300 microRNAs in 11 African American and Caucasian cell lines utilizing DiscovArray microRNA Microarray Chip. Validations of the most significant miRNAs were done by qRT-PCR. Characterization of the microRNA was carried out by performing MTT assay, Flow Cytometry, Western Blot, and Imunoflourescence.

Results: We identified 15 microRNAs that were differentially expressed between the African American and Caucasian cell lines. Further validations led to the identification of miR-152 which is significantly expressed among both groups. MiR-152 is thought to be responsible for inhibiting DNA methyltransferase 1 (DNMT1). Our results showed that miR-152 reduced cellular proliferation in PC-3, DU-145 and LNCaP prostate cancer cell lines. In addition, miR-152 inhibited DNMT1 protein expression as well as initiated G2-M cell cycle arrest.

Conclusion: Validation of these results indicates a significant difference in microRNA expression between African American and Caucasian prostate cancer. Furthermore, these results suggest that microRNAs may play a role in the advance progression seen in prostate cancer in African Americans. These findings are currently being validated in African American and Caucasian tissue samples. Research supported by G12 RR03059-21A1(NIH/RCMI), and CA118623 (NIH/NCI).

Citation Format: Shaniece Crystal Theodore, Melissa Davis, Rhim Jhong, Timothy Turner, Clayton Yates. Profiling miR-152 expression in African American prostate cancer cell lines. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr B38.
Abstract FO02-03: Breast cancer control in federally qualified health centers.
Authors: Calhoun Elizabeth A.
Published: August 2014

Patient Navigation is a patient-centric health care service delivery intervention, with the goal of eliminating barriers, which may occur across the health care continuum, from screening, to timely diagnosis and treatment of cancer, and through survivorship. Pioneered in Harlem, NY, patient navigation is being widely replicated nationally and is receiving considerable support for demonstration projects and research to test its effectiveness. Patient navigation has evolved as a strategy to reduce cancer health disparities by eliminating barriers to timely diagnosis and treatment of cancer. The largest and longest effort to test the efficacy of PN is the $25 million, five-year Patient Navigation Research Program (PNRP) undertaken by the National Cancer Institute (NCI). The Chicago patient navigation program, for example, was funded through the NCI PNRP to increase the proportion of patients reaching diagnostic resolution and reduce the time from abnormal screening test to definitive diagnostic resolution among low income underserved women with abnormal breast (n=352) or cervical (n=545) screening results. We found that compared to control subjects who received usual care, a higher percentage of navigated subjects reached a diagnostic resolution by 60 days (83.0% vs. 52.7%) for breast and by 365 days (98.7% vs. 81.0%) for cervical cancer. But, the effects of patient navigation are defined and measured in different ways across programs. In order to make meaningful comparisons across diverse programs, outcome measures must be concordant. Therefore, in March 2010, the National Patient Navigation Leadership Summit comprised of cancer clinicians, researchers, practicing public health and measurement experts, funders, and patient navigators, met to develop a national consensus on common outcomes to solidify the scientific evidence and efficacy of patient navigation using a principles from community-based participatory research. The goal of the Summit was to develop and propose core metrics to measure outcomes of navigation on individuals as well as populations across the continuum. The process used to engage all key stakeholders and current national efforts will be discussed along with the outcomes of this approach.

Funding: The Chicago Patient Navigation grant was supported by the National Institute of Health grant 1 U01 CA116875-01. The leadership conference and Cancer supplement were cosponsored by Pfizer Oncology, Livestrong (Lance Armstrong Foundation), Susan G. Komen for the Cure, the Oncology Nursing Society (ONS), the American College of Surgeons Commission on Cancer, the American Cancer Society, and AstraZeneca.

Citation Format: Elizabeth A. Calhoun. Breast cancer control in federally qualified health centers. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr FO02-03.
Abstract PL06-02: Inflammation, DNA mismatch repair, and colon cancer.
Authors: Carethers John M.
Published: August 2014

Colorectal neoplasia is driven by at least two pathogenic pathways for cancer development. Chromosomal instability, observed in ~80% of sporadic colorectal cancers, is named due to the rearrangement of chromosomes, resulting in aneuploid nuclei. The etiology for CIN is not known. A common finding is allelic mutation of a tumor suppressor gene, followed by loss of the remaining normal allele (termed loss of heterozygosity, LOH). Microsatellite instability (MSI), observed in up to 20% of sporadic colorectal cancers, is named for frameshifts (or instability) that occur at DNA microsatellite sequences. Cells remain diploid. The etiology for MSI is inactivation of DNA mismatch repair (MMR), an enzyme system functioning in the nucleus to repair interstrand nucleotide mispairs and loops of DNA that are formed on one strand at microsatellites. The specificity of mismatch recognition is directed by hMutSa and hMutSb; hMutSa (hMSH2-hMSH6 heterodimer) binds to single mispairs and single insertion-deletion loops, whereas hMutSb (hMSH2-hMSH3 heterodimer) binds larger insertion-deletion loops. MSI sporadic cancers are caused by hypermethylation of the MMR gene hMLH1's promoter, preventing its transcription and translation. With loss of hMLH1, MMR completely fails and mutations accumulate in the genome due to non-repair of DNA polymerase errors. Clinically, MSI tumors contain surrounding and intratumoral mononuclear inflammatory cells which are thought responsible in containing the tumor in place, leading to improved survival over same staged patients with non-MSI tumors. Although the types of inflammatory cells within MSI tumors have not been characterized, it is believed that neo-peptides from frameshifted proteins as a result of MMR failure are generated to attract mononuclear cells into the tumor, producing a protective immune response. Elevated microsatellite instability at selected tetranucleotide repeats (EMAST) is a genetic signature observed in 60% of sporadic colon cancers. Unlike MSI colorectal cancers in which hypermethylation of hMLH1 drives multiple target gene mutations, the cause of EMAST has been recently associated with reduced expression of hMSH3, which we have also observed in hamartomatous polyps and during the adenoma-to-carcinoma progression, and is hypothesized to be triggered as a consequence of inflammation with subsequent relaxation of MMR function. EMAST-positive human colorectal cancers are strongly associated with inflammation, particularly within tumor nests, but unlike MSI tumors, this inflammation is associated with advance staged colorectal cancer, implying reduced survival.

Citation Format: John M. Carethers. Inflammation, DNA mismatch repair, and colon cancer. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr PL06-02.
Abstract A27: Loss of PABPN1 and alternative polyadenylation yield poor prognosis in non-small cell lung cancer.
Authors: Ichinose Junji , Watanabe Kousuke , Sano Atsushi , Nagase Takahide , Nakajima Jun , Fukayama Masashi , Yatomi Yutaka , Ohishi Nobuya , Takai Daiya
Published: August 2014

Alternative polyadenylation (APA), which induces shortening of the 3'UTR, is emerging as an important layer in gene regulation. APA is involved in cell proliferation, development, and cancer. APA may lead to disruption of microRNA-mediated gene regulation in cancer cells via detachment of microRNA binding sites. We studied the correlation between the APA profile and the tumor aggressiveness in cases of lung cancer.

We selected the top 10 genes specifically showing significant 3'UTR shortening in lung cancer, using the package of the Bioconductor for probe-level analyses of expression microarrays. We established and evaluated the APA score by qRT-PCR in 147 clinical specimens of non-small cell lung cancer and compared the results with the clinical outcomes and expression levels of APA-related genes, including PABPN1, CPEB1, E2F1 and several proliferation markers (MKI67, TOP2A and MCM2).

High APA scores were correlated with an advanced tumor stage and poor prognosis (P < 0.001). Multivariate analysis identified the APA score as an independent prognostic factor (hazard ratio, 3.0; P = 0.03). Both loss of PABPN1 and gain of the proliferation markers were correlated with high APA scores and a poor prognosis, with suppression of PABPN1 exerting its influence independent of gain of the proliferation markers. Moreover, the APA score was correlated with the maximum standardized uptake value of the tumors on positron emission tomography (r = 0.53; P < 0.001).

Our results indicate that the loss of PABPN1, a recently identified suppressor of APA, promotes tumor aggressiveness by releasing the cancer cells from microRNA-mediated gene regulation.

Citation Format: Junji Ichinose, Kousuke Watanabe, Atsushi Sano, Takahide Nagase, Jun Nakajima, Masashi Fukayama, Yutaka Yatomi, Nobuya Ohishi, Daiya Takai. Loss of PABPN1 and alternative polyadenylation yield poor prognosis in non-small cell lung cancer. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr A27.
Abstract A32: RET fusion gene: Translation to personalized lung cancer therapy.
Authors: Kohno Takashi , Tsuta Koji , Tsuchihara Katsuya , Mizukami Tatsuji , Yoh Kiyotaka , Goto Koichi
Published: August 2014

Oncogenic RET fusion gene, occurring in 1–2% of LADCs, was recently identified by us and others as a new targetable driver gene in lung adenocarcinoma. Existing FDA-approved inhibitors of RET tyrosine kinase, such as vandetanib, show promising therapeutic effects both in vitro and in vivo, as well as in a few patients. A phase II clinical trial, investigating the therapeutic effects of vandetanib, has been started in Japan (UMIN00001009) in Q1 of 2013. The RET fusion screening is being conducted in > 120 hospitals throughout Japan by a consortium designated “LC-SCRUM (Lung Cancer Genomic Screening Project for Individualized Medicine in Japan)”. Approximately 4% of >300 EGFR-mutation negative NSCLC patients screened have been diagnosed as being positive for RET fusion, and the therapy of several patients has started. Positive responses to vandetanib have been observed as expected. In addition, the structure of breakpoints of RET fusion in lung adenocarcinoma indicates that the different molecular processes generate oncogenic RET fusions between lung adenocarcinoma and papillary thyroid carcinoma. Etiology and therapeutic significance of RET fusion in lung adenocarcinoma will be discussed.

Citation Format: Takashi Kohno, Koji Tsuta, Katsuya Tsuchihara, Tatsuji Mizukami, Kiyotaka Yoh, Koichi Goto. RET fusion gene: Translation to personalized lung cancer therapy. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr A32.
Abstract A37: Ectopic claudin 6 and 18.2 expression as potential treatment target in non-small cell lung cancer.
Authors: Mattsson Johanna SM , Micke Patrick , Edlund Karolina , Lohr Miriam , Jirström Karin , Berglund Anders , Botling Johan , Rahnenfuehrer Jörg , Marincevic Millaray , Pontén Fredrik , Ekman Simon , Hengstler Jan G. , Wöll Stefan , Sahin Ugur , Türeci Özlem
Published: August 2014

Claudins are central components of tight junctions that regulate epithelial cell barrier function and polarity. Altered claudin expression patterns have been demonstrated in numerous cancer types and lineage-specific claudins have been proposed as therapy targets. The objective of this study was to assess claudin 6 (CLDN6) and claudin 18 isoform 2 (CLDN18.2) expression in human non-small cell lung cancer (NSCLC).

Transcript levels were evaluated based on gene expression microarray data from a fresh-frozen NSCLC tissue cohort (n=196). Protein expression levels of CLDN6 and CLDN18.2 were examined by immunohistochemistry on a tissue microarray (n=355), and analyzed with regard to frequency distribution and association with clinical parameters.

High mRNA levels of CLDN6 and total CLDN18 were observed in subsets of non-squamous lung carcinomas. Correspondingly, distinct membranous positivity of CLDN6 (6.5%) and CLDN18.2 (3.7%) was displayed by virtually non-overlapping subgroups of adenocarcinomas and large cell carcinomas, while pneumocytes and bronchial epithelial cells were consistently negative. CLDN18.2 positive tumors were enriched among slowly proliferating, TTF1-negative adenocarcinomas, suggesting that isoform-specific claudin expression may delineate a specific subtype. Noteworthy, high CLDN6 mRNA as well as protein expression was associated with worse prognosis in lung adenocarcinoma.

In conclusion, distinct CLDN6 and CLDN18.2 positivity was observed in minor subsets of non-squamous NSCLC, indicating that tumor-specific claudin expression may define molecular subtypes associated with clinical parameters. These findings encourage further clinical exploration of targeting ectopic claudin expression as a valuable treatment concept in NSCLC.

Citation Format: Johanna SM Mattsson, Patrick Micke, Karolina Edlund, Miriam Lohr, Karin Jirström, Anders Berglund, Johan Botling, Jörg Rahnenfuehrer, Millaray Marincevic, Fredrik Pontén, Simon Ekman, Jan G. Hengstler, Stefan Wöll, Ugur Sahin, Özlem Türeci. Ectopic claudin 6 and 18.2 expression as potential treatment target in non-small cell lung cancer. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr A37.
Abstract B28: Histone methylation-mediated silencing of mir-139 enhances an aggressive phenotype of non-small cell lung cancer.
Authors: Watanabe Kousuke , Sunohara Mitsuhiro , Amano Yosuke , Ishikawa Rie , Ichinose Junji , Nakajima Jun , Fukayama Masashi , Yatomi Yutaka , Nagase Takahide , Ohishi Nobuya , Takai Daiya
Published: August 2014

MicroRNA expression is frequently altered in human cancers, and some microRNAs act as oncogenes or tumor suppressors. Mir-139 has recently been reported to function as a tumor suppressor in hepatocellular carcinoma and gastric cancer, but its function in non-small cell lung cancer (NSCLC) and the mechanism of its suppression have not been studied in detail. Mir-139 was suppressed frequently in lung cancer cell lines and primary NSCLCs. Mir-139 was silenced with its host gene PDE2A by histone methylation, which was independent of DNA methylation. In primary NSCLCs, decreased expression of mir-139 was significantly associated with distant lymph node metastasis and histological invasiveness (lymphatic invasion and vascular invasion) on both univariate and multivariate analyses. Overexpression of mir-139 suppressed the proliferation of lung cancer cells. Collectively, these results suggest that histone methylation-mediated silencing of mir-139 enhances an aggressive phenotype of lung cancer.

Citation Format: Kousuke Watanabe, Mitsuhiro Sunohara, Yosuke Amano, Rie Ishikawa, Junji Ichinose, Jun Nakajima, Masashi Fukayama, Yutaka Yatomi, Takahide Nagase, Nobuya Ohishi, Daiya Takai. Histone methylation-mediated silencing of mir-139 enhances an aggressive phenotype of non-small cell lung cancer. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr B28.
Abstract B36: Synthesizing new proteins from 3-dimensional spheroids, compare to 2-dimensional cell line culture.
Authors: KIM KI-UP , Koo So-My
Published: August 2014

Introduction: Researches are basically in vitro. However, their results apply to in vivo were disappointed. That may be caused by 3-dimensional structure, not pure cell components, and cell to cell/matrix interactions. If artificial organisms, multicellular tumor spheroids (MCTS), have similar cell components, it may be closer to tumor and more advanced model. The represented protein from 2- and 3-dimensional culture may be different because their milieu is changed.

Objective: We tried a multicellular tumor spheroids (MCTS) from cancer cell line, fibroblasts from human, and PBMC by combination or singly as a model to cancer research. And we tested the differences from represented proteins at 2- and 3-dimensional condition from A549 cancer cell line.

Method: Cell from 3 conditions were cultured to agarose coated plate singly or combined at DME media. Their formation of spheroids were observed daily by inverted microscope and got samples serially for 4 weeks. Cell components from combined spheroids were stained immunohistochemically by their specific antibody. Proteins, which were cultured from 2-dimension and 3-dimension at 3 day from A549 cancer cell line, were loaded by 2-dimensional gel electrophoresis and were analyzed by MALDI-TOF.

Result: Cells were conglomated and made clusters except PBMC within a few days and formed spheroids between 4 to 7 days. The mixed cluster with A549, fibroblast and PBMC were formed round shape. Cell components from spheroids had been confirmed by immunohistochemical stain. Compare to 2-dimensional culture, 23 proteins by 2-dimensional gel electrophoresis were newly detected from spheroids. The most prominent protein was heat shock protein 90.

Conclusion: MCTS is a new model for tumor research, and heat shock protein 90 is an important role for 3-dimensional structure.

Citation Format: KI-UP KIM, So-My Koo. Synthesizing new proteins from 3-dimensional spheroids, compare to 2-dimensional cell line culture. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr B36.
Abstract A12: Regulation of ovarian cancer OVCAR-3 cell proliferation and viability by calcium/calmodulin-dependent protein kinase kinase 2
Authors: Gocher Angela M. , Azabdaftari Gissou , Edelman Arthur M.
Published: August 2014

Protein kinases play crucial roles in cancer progression and are considered potential targets for novel anti-cancer therapeutics. Oncogenic kinases mediate a variety of events characteristic of the malignant phenotype including transcriptional activation, accelerated cell proliferation and enhanced cellular survival. Ca2+/Calmodulin-dependent Protein Kinase Kinase 2 (CaMKK2) has been implicated as a signaling mechanism in prostate and breast cancers, but has not been studied in ovarian cancer (OvCa). We report here the following. CaMKK2 expression is greatly increased in high grade serous papillary cystadenocarcinoma compared to benign tissue. Knockdown of CaMKK2 expression by RNA interference in OvCa OVCAR-3 cells resulted in slowing of cell growth and decreased number of cells entering S phase. At the molecular level, CaMKK2 knockdown led to significant decreases in cyclin D1 expression at both mRNA and protein levels and to a drop in phosphorylation of the retinoblastoma tumor suppressor (Rb) at Ser 807/811. These results indicate that CaMKK2 expression in OVCAR-3 OvCa cells is required for optimal G1/S phase cell cycle progression and proliferation. CaMKK2 knockdown also resulted in a significant decrease in OVCAR-3 cell survival and an increase in both Poly ADP Ribose Polymerase (PARP) cleavage (inactivation) and in the activity of executioner Caspases-3/7 indicating that CaMKK2 knockdown in OVCAR-3 cells results in apoptosis. Preliminary data showed a decrease in phosphorylation of the activation site of Akt (Thr 308) in CaMKK2 depleted cells suggesting that the G1/S phase cell cycle arrest and apoptosis in CaMKK2 silenced cells may occur either directly or indirectly through an Akt-dependent pathway. Altogether these data show that CaMKK2 is required for optimal growth and viability of OVCAR-3 cells and furthermore imply that CaMKK2 may be a promising and novel therapeutic target for OvCa.

Citation Format: Angela M. Gocher, Gissou Azabdaftari, Arthur M. Edelman. Regulation of ovarian cancer OVCAR-3 cell proliferation and viability by calcium/calmodulin-dependent protein kinase kinase 2. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A12.
Abstract A38: DDB2 suppresses tumorigenicity of ovarian cancer cells through reducing the subpopulation of cancer stem cells
Authors: Han Chunhua , Zhao Ran , Kroger John , Liu Xingluo , Wang Qi-En
Published: August 2014

Ovarian cancer is an extremely aggressive disease associated with a high percentage of recurrence and chemotherapy resistance. Damaged DNA binding protein 2 (DDB2) is a 48-kDa protein originally identified as a component of the damage-specific DNA-binding heterodimeric complex DDB. Besides the known ability of DDB2 protein to bind ultraviolet (UV)-damaged DNA and serving as the initial damage recognition factor during nucleotide excision repair (NER). DDB2 was also reported to be involved in the promotion of apoptosis to reduce cisplatin resistance of ovarian cancer cells, control of cell migration, invasiveness and breast tumor progression, as well as suppression of metastasis of colon cancer through a transcriptional regulatory mechanism. Here we show that DDB2 overexpression in human ovarian cancer cell line CP70 suppressed its capability to recapitulate tumors in athymic nude mice, as well as the growth of these cells cultured in semisolid media. Flow cytometry analyses indicate that DDB2 overexpression in CP70 cells reduced the abundance of CD117+ cells and ALDH+ cells, which are believed to be markers of cancer stem cells (CSCs) in ovarian cancer. In contrast, downregulation of DDB2 in ovarian cancer cell line A2780 increased the percentage of ALDH+ cells. In addition, we analyzed the expression level of DDB2 in the putative CSCs isolated from various ovarian cancer cell lines, and demonstrated that DDB2 expression is decreased in the CSCs in comparison with their parental bulk tumor cells. Overexpression of DDB2 in the ovarian CSCs reduced the expression of CSC markers, e.g., Sox2 and Nanog. In addition, overexpression of DDB2 in CSCs isolated from ovarian cancer cell line SKOV-3 also decreased the tumorigenicity of these cells in NOD/SCID mice. In summary, our data suggest that DDB2 suppresses tumorigenicity of ovarian cancer cells through reducing the CSCs pool in cancer cells. Thus, increasing the expression of DDB2 may provide a molecular strategy to inhibit the recurrence of ovarian cancer. (Supported by NIH R01 grant CA151248 to QEW)

Citation Format: Chunhua Han, Ran Zhao, John Kroger, Xingluo Liu, Qi-En Wang. DDB2 suppresses tumorigenicity of ovarian cancer cells through reducing the subpopulation of cancer stem cells. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A38.