bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 571: Prevention of breast cancer by delaying promotion and progression
Authors: Arumugam Arunkumar , Boopalan Thiyagarajan , Parada Jacqueline , Das Trinath , Suman Suman , Lakshmanaswamy Rajkumar
Published: August 2012

A full term pregnancy early in life reduces the risk of breast cancer in women. A similar phenomenon is also observed in rats and mice. Short-term treatment with pregnancy levels of estradiol is also highly effective in preventing mammary carcinogenesis. In the current study our objective was to determine whether short-term treatment with pregnancy levels of estradiol conferred protection against mammary carcinogenesis by blocking initiation or promotion. Rats were injected with N-methyl-N-nitrosourea at 7 weeks of age and treated with 20 µg, 100 µg, 200 µg or 30 mg of estradiol in silastic capsules for 3-weeks. The experiments were terminated 9 months post carcinogen treatment. Mammary gland wholemounts were prepared at termination and examined for the presence of latent microscopic mammary cancers. Short-term treatment with pregnancy levels of estradiol drastically reduced the incidence of overt mammary cancers. 100 µg, 200 µg and 30 mg doses of estradiol resulted in levels of estradiol equivalent to pregnancy level and were effective in preventing overt mammary cancer incidence compared to control or 20 µg estradiol treatment which did not result in pregnancy levels of estradiol in the circulation. Although a significant reduction of overt cancers was observed in the pregnancy levels of estradiol treated groups, there was no difference in the incidence of microscopic mammary cancers between the estradiol treated and the controls. Proliferation of microscopic mammary cancers was examined using immunohistochemistry for cyclin D1 expression. Proliferation in the microscopic mammary cancers of the protected groups was significantly lower (∼ 2-3 fold) than the microscopic mammary cancers in the unprotected groups. These findings clearly demonstrate that short-term treatment with pregnancy levels of estradiol confers protection against mammary cancer development by blocking promotion and progression of carcinogen initiated cells.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 571. doi:1538-7445.AM2012-571
Abstract 5734: Role of the inflammasome complex in Cr(VI)-induced lung injury and inflammation
Authors: Hopkins Lauren , Forbes Thomas , Schneider Brent , Constant Stephanie L. , Leitenberg David , Schwartz Arnold M. , Patierno Steven R. , Ceryak Susan
Published: August 2012

Certain particulate hexavalent chromium [Cr(VI)] compounds are human respiratory carcinogens that release genotoxic soluble chromate, leading to fibrosis, fibrosarcomas, adenocarcinomas and squamous cell carcinomas of the lung. While considerable information exists regarding Cr(VI) genotoxicity in cell culture, the mechanisms by which Cr(VI) causes lung injury and carcinogenesis in vivo are still unknown. We postulate that early inflammatory processes and mediators may contribute to the etiology of Cr(VI) carcinogenesis. We have previously established that intranasal (IN) particulate Cr(VI) administration in Balb/c mice induced a pronounced innate inflammatory response in the lung. Our present aim was to directly test the contribution of inflammasome-mediated inflammatory processes to chromate-mediated lung cancer development. We used WT and inflammasome-deficient (ASC knockout) BALB/c mice for weekly IN delivery of either saline or 10 ug particulate basic zinc chromate, which is an intermediately water soluble chromate typically encountered in mining/chromate production facilities and which is also present as an environmental atmospheric contaminant in urban areas surrounding ferrochrome production facilities. After 9 weeks, immune cells, cytokines, MMPs and pathologic features of lung injury and inflammation were measured in airway lavage fluid and lung tissue. Inflammasome-deficient mice exhibited a markedly reduced number of airway leukocytes in response to Cr(VI) challenge when compared to their WT counterparts, which was particularly evident for macrophages. Moreover, the Cr-induced increase in airway levels of IL6 (8-fold), CXCL/KC (3-fold), as well as pro-MMP9 (100-fold) was significantly attenuated in the inflammasome-deficient mice. In contrast, histological examination of lung tissue in animals challenged with chromate revealed a similar increase in peribronchiolar inflammation in both WT and ASC-/- mice, suggesting that Cr-induced lung inflammation may involve ASC-dependent and independent mechanisms, and that tissue infiltration may be less impacted by ASC-dependent mechanisms. In conclusion, particulate chromate is a potent inducer of inflammatory responses in the lung, mediated in part through the inflammasome complex. We postulate that these early inflammatory processes may contribute to the etiology of Cr(VI) carcinogenesis. The findings may also be relevant to other lung particulates that induce injury and cancer. Supported by NIH grants CA107972 and ES017334 to SC and ES017307 to SRP.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5734. doi:1538-7445.AM2012-5734
Abstract 5747: Elucidating the mechanisms by which Snail transcription factor promotes resistance to chemotherapy in breast carcinomas
Authors: Smith Bethany N. , Nagappan Peri , Chetram Mahandranauth , Taliaferro-Smith Latonia , Saintil Tamar , Yates Clayton , Hinton Cimona , Odero-Marah Valerie
Published: August 2012

Snail (Snail1) is a zinc finger transcription factor that can induce EMT and is expressed at high levels in tumors. Maspin is a potential tumor suppressor, whose expression is lost as breast and prostate tumors progress during EMT. Maspin can be transcriptionally repressed by androgen receptor (AR) in prostate cancer cells. We hypothesized that overexpression of Snail will inhibit maspin expression and confer resistance to chemotherapy. Initially, we examined the expression of Snail and maspin in a panel of breast epithelial and breast cancer cells by RT-PCR and Western blot analysis. Preliminary results suggest that breast cancer cells express variable levels of Snail that is higher in breast cancer cells than in the normal MCF10A cells. We then utilized MCF-7 cells transfected stably with an empty Neo vector (MCF-7 Neo) or constitutively active Snail cDNA (MCF-7 Snail) that have been shown previously to represent an EMT model, and examined maspin, estrogen receptor alpha (ER-α) and AR levels by western blot analysis. MCF-7 Snail cells had upregulated levels of Snail and lower levels of maspin, ER-α and AR, as compared to MCF-7 Neo. MCF-7 Neo and MCF-7 Snail cells were also xenografted into nude mice and tissue sections stained immunohistochemically for Snail, maspin, and ER-α. Tumor volumes of MCF-7 Snail tumor xenografts were significantly larger than the MCF-7 Neo xenografts. MCF-7 Snail tissue sections expressed higher levels of Snail and lower levels of maspin and ER-α as compared to MCF-7 Neo sections. MCF-7 Neo and MCF-7 Snail cells were also treated with estradiol (E2, 0.01uM), tamoxifen (TAM, 10uM), and docetaxel (DOX, 1uM) individually; and in combination with E2 plus TAM and TAM plus DOX for periods of 24h and 72h to analyze changes in cell morphology and EMT marker expression. No effect on cell morphology or cell death was observed in MCF-7 Snail cells after TAM treatments, whereas TAM induced cell death in MCF-7 Neo. Expression of Snail was increased with E2 treatments and decreased with TAM, DOX, and combination treatments in MCF-7 Neo and MCF-7 Snail. AR expression decreased further in MCF-7 Snail cells and MCF-7 Neo following treatments with TAM and DOX. Overall, the Snail overexpression appears to promote resistance to TAM and DOX chemotherapeutic agents. The mechanism of Snail-regulated EMT needs to be investigated further to determine changes in breast cancer progression.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5747. doi:1538-7445.AM2012-5747
Abstract 578: Apigenin blocks medroxyprogesterone acetate-dependent progression of BT-474 human breast tumor xenografts by inducing apoptosis
Authors: Mafuvadze Benford , Liang Yayun , Besch-Williford Cynthia L. , Hyder Salman M.
Published: August 2012

Recent clinical and epidemiological evidence suggests that hormone replacement therapy (HRT) containing both estrogen and progestin increases the risk of metastatic breast cancer in post-menopausal women compared with estrogen monotherapy or placebo treated women. The biological mechanisms behind this phenomenon remain obscure. We showed that medroxyprogesterone acetate (MPA), a commonly used progestin in HRT, increases the production of the potent angiogenic growth factor VEGF in breast cancer cells. The anti-progestin RU-486 blocks this effect, suggesting the involvement of progesterone receptors in the process (Int J Cancer, 2001, 92:469). This led to our hypothesis that progestins increase the angiogenic potential of latent tumorigenic cells in the breast, leading to development of palpable tumors. Using a xenograft model that was developed in our laboratory (Cancer Res., 2007, 67:9929), we previously showed that progestins promote the growth and development of BT-474 human xenograft tumors, as well as increasing BT-474 cell metastasis. In this study, we sought to determine whether apigenin, a low molecular weight flavonoid with known anti-carcinogenic properties, inhibits MPA-induced growth of BT-474 xenografts in nude mice. BT-474 human breast cancer cells were inoculated in immune-deficient mice that had been pre-inoculated with estradiol pellets. As was previously reported with this model, estradiol supported a short burst of tumor cell growth, which was followed by tumor regression. Implantation of MPA pellets rescued and stimulated further tumor growth. Administration of apigenin (50 mg/kg i.p.) inhibited the MPA-induced progression and development of BT-474 xenograft tumors. Immunohistochemical analysis revealed that the anti-tumor effects of apigenin occur through induction of tumor cell apoptosis, as measured using TUNEL assay, and also in part by suppression of cell proliferation (Ki67). Apigenin therefore appears to have therapeutic potential against progestin-dependent breast cancer and might be considered as a neutraceutical for treating progestin-dependent tumors in women already exposed to progestins. This study was supported by a COR award from the College of Vet Medicine, and research funds from RADIL, University of Missouri.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 578. doi:1538-7445.AM2012-578
Abstract 589: Benzyl isothiocyanate effectively inhibits solid tumor growth and lung metastasis of 4T1 mammary carcinoma cells in BALB/c mice fed on a high-fat diet
Authors: Kim Minhee , Park Jung Han Yoon
Published: August 2012

Benzyl isothiocyanate (BITC) is a hydrolysis product of glucotropaeolin, a compound found in cruciferous vegetables. We previously observed that chronic consumption of a high-fat diet increased the breast cancer progression and lung metastasis in the 4T1 orthotopic BALB/c mouse model. In the present study, we determined whether BITC inhibits high-fat diet-induced acceleration of breast cancer growth and metastasis in the 4T1 model. 4-week old, female BALB/c mice were fed on a high-fat diet (HFD, 60 kcal% fat) or control diet (CD, 10 kcal% fat) and BITC was administered daily with oral gavage (0, 5, or 10 mg/kg body weight/day). After 16 weeks, 4T1 cells (5 × 104 cells) were injected into the mammary fat pads of syngeneic, female, BALB/c mice and the mice were continuously fed on the same diets and BITC. 26 day after the cancer cell injection, animals were killed. The weights of tumors and lungs were significantly increased in the HFD group as compared to the CD group, and the increases were suppressed by BITC treatment. Additionally, chronic consumption of the HFD markedly increased the number and volume of tumor nodules in the lung; the increases were markedly suppressed by BITC treatment. Immunohistochemical staining of tumor tissues revealed that the expression of platelet endothelial cell adhesion molecule-1 (PECAM-1, CD31, an angiogenesis marker), vascular endothelial growth factor (VEGF)-A, LYVE-1 (lymphatic vessel endothelial receptor-1), VEGF-D, Ki67, cyclin-dependent kinase 2, cyclin A, cyclin D1, and hypoxia-inducible factor 1α (HIF-1α) was markedly increased in the HFD group as compared to the CD group; the increases were blocked by BITC treatment. Chronic consumption of the HFD reduced TUNEL-positive apoptotic cells, which was prevented by BITC treatment. The present results demonstrate that BITC suppressed HFD-stimulated breast cancer progression, which may have been mediated via the suppression of cell cycle progression, tumor angiogenesis and lymph angiogenesis, and induction of apoptosis.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 589. doi:1538-7445.AM2012-589
Abstract 595: Non-motorized voluntary running does not affect experimental and spontaneous metastasis in mice
Authors: Yan Lin , DeMars Lana C.
Published: August 2012

The present study investigated the effects of non-motorized voluntary running on experimental metastasis of B16BL/6 melanoma and spontaneous metastasis of Lewis lung carcinoma (LLC) in male C57BL/6 mice. After 9 weeks of running, mice (n = 30 per group) received an intravenous injection of B16BL/6 cells or a subcutaneous injection of LLC cells, and then they continued with their running activities. Experiments were terminated 2 weeks after the intravenous injection of B16BL/6 cells or 2 weeks after surgical removal of the primary tumor from mice subcutaneously injected with LLC cells. Mice in the running group ran an average of 4-6 km/day for the duration of the experiment. Voluntary running reduced body weight compared with sedentary controls, but there were no differences in the number and size of lung metastases between groups with either model. Voluntary running significantly reduced plasma insulin and leptin levels and increased adiponectin level in mice with and without LLC compared with their respective sedentary controls. Having LLC significantly increased plasma concentrations of vascular endothelial growth factor (VEGF), platelet-derived growth factor-BB (PDGF-BB), PDGF-AB and monocyte chemotactic protein-1 (MCP-1) in mice. Voluntary running significantly increased plasma PDGF-BB and PDGF-AB, but not VEGF and MCP-1, in mice with LLC compared with their sedentary counterparts. In summary, non-motorized voluntary running was favorable to body weight and the expression of related adipokines, but at 4-6 km/day it did not affect either experimental or spontaneous metastasis in mice.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 595. doi:1538-7445.AM2012-595
Abstract 615: Apigenin regulates prostate cancer matrix composition and cell attachment through an integrin alpha 1 dependent pathway
Authors: Franzen Carrie A. , Pelling Jill C. , Bergan Raymond C.
Published: August 2012

Prostate cancer (PCa) mortality is primarily attributed to metastatic rather than primary, organ-confined disease. Acquiring a motile and invasive phenotype is an important step in the development of metastasis. This step involves remodeling of the extracellular matrix (ECM) and of cell-matrix interactions, cell movement mediated by the actin cytoskeleton, and activation of focal adhesion kinase (FAK)/Src signaling. Epidemiologic studies suggest that the metastatic behavior of PCa may be an ideal target for chemoprevention. The natural flavone apigenin is known to have chemopreventive properties against many cancers, including PCa. Building upon our previous findings showing that apigenin inhibits cell motility and invasion of PCa cells through the FAK/Src signaling pathway, here we study the effect of apigenin on integrin receptors, cell attachment, and ECM composition. By using an alpha/beta integrin-mediated cell adhesion array, we found that integrin alpha 1 (ITGA1) was the only integrin subunit to be down-regulated by apigenin in PC3-M cells. ITGA1, whose only binding partner is integrin beta 1, is a receptor for collagen and laminin. Integrin α1α1 gives cells the ability to attach to collagenous substrata. As collagen and laminin are important regulators of PCa cell survival, growth and metastasis to bone, we next elucidated the effect of apigenin on PC3-M cell attachment to laminin 1 and collagen IV. We found that apigenin decreases cell attachment to both of these ECM molecules, suggesting a potential anti-tumorigenic mechanism. It has been shown that integrin α1α1 can regulate the synthesis of collagen. So we next tested whether apigenin can alter the ECM deposited by PC3-M cells. We first tested whether ECM deposited by apigenin-treated cells provided the same adhesive support to PCa cells as the ECM deposited by the untreated cells. Interestingly, even cells not treated with apigenin did not attach and spread well on the ECM deposited by apigenin-treated cells, indicating that apigenin treatment changes the composition of the ECM. Using Western blot to evaluate differences in the composition of matrix deposited by control cells and apigenin-treated cells, we found that apigenin-treated cells produce much less collagen I and IV, thus correlating with the decrease in adhesion and spreading. These results demonstrate that the chemopreventive bioflavonoid apigenin may inhibit PCa cell adhesion through a combined effect on integrin α1α1 cell surface expression and ECM deposition.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 615. doi:1538-7445.AM2012-615
Abstract 622: Estrogen plus progesterone and colorectal cancer incidence and mortality in the Women's Health Initiative
Authors: Simon Michael S. , Chlebowski Rowan T. , Wactawski-Wende Jean , Johnson Karen C. , Muskovitz Andrew , Kato Ikuko , Young Alicia , Hubbell F Allan
Published: August 2012

Background: During the intervention period in the Women's Health Initiative (WHI) trial, estrogen plus progestin use was associated with lower colorectal cancer incidence but the cancers were diagnosed at substantially higher stage. To assess the long term influence of estrogen plus progestin on this disease, analyses were conducted over the entire follow-up period. Methods: The WHI study is a randomized, double-blind, placebo-controlled, clinical trial involving 16,608 postmenopausal women aged 50-79 years with an intact uterus who were randomly assigned to a once-daily tablet of 0.625 mg conjugated equine estrogen plus 2.5 mg medroxyprogesterone acetate (N=8,506) or matching placebo (N=8,102). We assessed incidence, tumor characteristics, and mortality rates for invasive colorectal cancers. Analyses were by intention to treat. The study is registered with clinical trials CT.gov NCT00000611. Findings: After a mean of 5.6 years (SD 1.03) of therapy and 11.6 (SD 3.1) years of total follow-up, 118 women in the combined hormone therapy group were diagnosed with colorectal cancer vs 145 in the placebo group (incidence/year 0.12% vs 0.16%; hazard ratio [HR] 0.72, 95% confidence interval (CI), 0.56-0.94; P=0.014). Bowel screening exams were comparable between groups throughout. Cancers in the combined hormone therapy group more commonly had positive lymph nodes (53.4% vs 30%, P=0.007) and were at higher stage (regional or distant, 68.8% vs 51.4%, P=0.003). Somewhat more women died from colorectal cancer in the combined hormone therapy group (37 vs 27 deaths; 0.04% vs 0.03%; HR 1.29, 95% CI 0.78-2.11, P=0.320). Interpretation: Although estrogen plus progestin use was associated with lower colorectal cancer incidence, the cancers were at more advanced stage and no trend for colorectal cancer mortality reduction emerged. These findings, suggestive of diagnostic delay, do not support a clinically meaningful benefit for combined hormone therapy on colorectal cancer risk.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 622. doi:1538-7445.AM2012-622
Abstract 633: Synergistic interplay between long-term overweight and long menstrual years in endometrial cancer
Authors: Lu Lingeng , Lee Shanming , Mayne Susan , Irwin Melinda , Cartmel Brenda , Risch Harvey , Yu Herbert
Published: August 2012

Long-term exposure to estrogen is one of the established mechanisms underlying the development of endometrial cancer. Early menarche, late menopause, low number of pregnancies, and obesity, as risk factors of endometrial cancer, are all linked to this mechanism. However, the synergy among these factors is still less clear. To evaluate the interplay among long-term overweight, menstrual and reproductive features in endometrial cancer, a population-based case-control study was conducted with 668 incident cases and 674 age-matched population controls. Information on menstrual and reproductive features, anthropometric measurements in each decade of adult life as well as hormone replacement therapy was ascertained through a structured questionnaire administered by interviewers. Unconditional logistic regression model was used to examine the associations of these factors with endometrial cancer. As expected, the results show that early menarche, late menopause, low number of pregnancies and live births, and long-term overweight were associated with increased risk. To assess all the menstrual and reproductive factors together, we calculated net menstrual years by subtracting age at menarche from age at menopause, which was further subtracted by the total years of pregnancy. Women with long net menstrual years (> 38 years) had nearly two-fold increases in risk of endometrial cancer (95% CI: 1.43-2.41) compared to those with shorter years (<35 years). Approximately a 3.5-fold increase in risk (95% CI: 2.79-7.04) was observed in those who were overweight since ages 20's or 30's compared to those who maintained BMI under 25 throughout life. Women with both long net menstrual years and long-term overweight combined had over 7-fold increases in risk compared to those with short years and normal weight. These finding suggest that long-term overweight and long menstrual years may have a synergistic effect on endometrial cancer risk.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 633. doi:1538-7445.AM2012-633
Abstract 652: Reproductive and hormonal factors and ovarian cancer: Case-control study
Authors: ma Seunghyun , Park Sue K. , Yoo Keun-Young , Kim Tae Joong , Kim Byoung-Gie , Kim Yong-Man , Kim Jae Weon
Published: August 2012

Backgrounds: Menstrual, reproductive and hormonal factors have been related to ovarian cancer risk, but further quantification of their role in various populations is required. Patients and methods: Cases were 77 women, below age 79, with incident, histologically confirmed epithelial ovarian cancer, and 117 women with, histologically confirmed benign ovarian tumor and controls 776 women, age matched controls The study was conducted from 2009 to 2010 in five hospitals in Seoul, South Korea. Data were obtained through in-person interviews and analysis was conducted using unconditional logistic regression Results: A statistically significant inverse association was observed between parity and ovarian cancer risk and between parity and benign ovarian tumor (Odds ratio [OR] = 0.18; 95% confidence interval [CI] = 0.06-0.50, OR=0.08, CI (0.02-0.30))No consistent association was observed with time since first or last birth, nor with spontaneous or induced abortions Breastfeeding was associated with a significant reduction in risk of ovarian cancer and benign neoplasm. (OR=0.33, CI (0.17-0.68), OR=0.42 CI(0.34-0.94)) Conclusion: This uniquely asian study confirms and further quantities the relation between hormonal and reproductive factors and ovarian cancer.The pattern of risk observed cannot be totally explained by a role of ovulation in ovarian carcinogenesis.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 652. doi:1538-7445.AM2012-652
Abstract 659: Intake of fiber and fiber-rich plant foods associated with lower risk of renal cell carcinoma in a large U.S. cohort
Authors: Daniel Carrie R. , Chow Wong-Ho , Park Yikyung , Graubard Barry I I. , Hollenbeck Albert R. , Sinha Rashmi
Published: August 2012

Renal cell carcinoma (RCC) accounts for nearly all adult kidney malignancies. The age-adjusted incidence of RCC has more than doubled over the last three decades in the U.S., mirroring the growing epidemic of obesity, which along with smoking comprise the most well-established RCC risk factors. Plant-based and fiber-rich diets high in vegetables, fruits, and whole grains are recommended for the prevention of cancer, as well as chronic conditions positively associated with RCC incidence, such as hypertension and diabetes. Thus, diet may play a role in RCC etiology directly and/or indirectly. In a large prospective cohort of U.S. men and women, we comprehensively investigated dietary intake of a range of plant foods and their nutritional components in relation to RCC risk. We further examined whether associations varied by history of hypertension or diabetes, body mass index, smoking status, or alcohol intake. At baseline (1995-1996), 492,186 participants of the National Institutes of Health-AARP Diet and Health Study completed a self-administered questionnaire of demographics, diet, lifestyle, and medical history. Over 9 (mean) years of follow-up we identified 1,814 incident cases of RCC. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated within quintiles (Q) using multivariable Cox proportional hazards regression. Intake of legumes, whole grains, and cruciferous vegetables were associated with a statistically significant 16-18% reduced risk of RCC. Conversely, refined grain intake was positively associated with RCC risk [Q5 vs. Q1, HR and 95% CI: 1.19 (1.02-1.39); P-trend =0.04] and we found no association with fruit intake. These findings were consistent with the strong inverse association we observed for total dietary fiber intake [Q5 vs. Q1, HR and 95% CI: 0.81 (0.69-0.95); Ptrend =0.005], as well as fiber derived from various dietary sources. The association between fiber intake and RCC did not vary substantially by smoking status [Q5 vs. Q1, HR and 95% CI: 0.65 (0.49-0.87) and 0.50 (0.25-1.02) in never vs. current smokers, respectively], history of hypertension [0.73 (0.52-1.02) and 0.75(0.57-1.00) in negative vs. positive history, respectively], or other major risk factors. In conclusion, intake of fiber and fiber-rich plant foods was associated with a significantly lower risk of renal cell carcinoma in this large U.S. cohort.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 659. doi:1538-7445.AM2012-659
Abstract 692: Prognostic indicators associated with breast cancer molecular subtypes in African-American women
Authors: Ricks-Santi Luisel J. , Esnakula Ashwini , Frederick Wayne A.I. , Dunston Georgia M. , Naab Tammey
Published: August 2012

Background: Overexpression of Fascin, Endoglin (CD105), and Beta-Catenin has been found to be associated with unfavorable prognosis and progression in hormone-receptor negative breast carcinomas. Specifically, fascin promotes cell motility, while Beta-catenin is involved in cancer invasion, cellular transformation, and metastasis. CD105 is selectively upregulated in small, immature tumor vessels in malignant tumors. The objective of this study was to correlate fascin, CD105, and Beta-Catenin protein expression with clinicopathological factors including age, grade, tumor size, stage, regional node status, survival, and with the four major molecular breast cancer subtypes (luminal A, luminal B, HER2 positive, and Triple Negative [TN]). Methods: Tissue microarrays (TMAs) were constructed from optimally-fixed formalin-fixed, paraffin-embedded tumor blocks from primary breast carcinomas in 203 African-American females. Sections were stained with antitibodies against fascin, CD105, and beta-catenin. The sections were evaluated for the intensity of reactivity (0-3) and the percentage of reactive cells. Cases were categorized as having negative/weak (score <10) or moderate/strong (score >10) fascin expression, negative (score=0) or positive (score>0) CD105 (in tumor cells only) and beta-catenin (cytoplasmic and nuclear) expression. Bivariate analysis was done via χ2 analysis and survivability data was calculated via the generation of Kaplan-Meier curves (SPSS v19). Statistical significance was assumed if P < 0.05. Results: On the TMA, there were 67 triple negatives, 88 Luminal As, 29 Luminal Bs, and 18 Her2 overexpressing cancers. The mean age for the patients in the study was 57.65. Fascin expression was significantly linked to the triple negative subtype (p<0.0001), ER negativity (p<0.0001), PR negativity (0.0001), and Grade III differentiation (p=0.03). CD105 cytoplasmic expression significantly correlated with HER2 positive subtype (p<0.0001), Luminal B subtype (0.01), HER2 positivity (p<0.0001), tumor size (p<0.01) and was associated with decreased disease-free survival (p=0.038). Cytoplasmic beta-catenin expression was significantly associated with triple negative subtype (p<0.03), HER2+ subtype (p<0.001), ER negativity (p<0.001), PR negativity (p<0.001), and HER2 negativity (p=0.03). Conclusions: Our results indicate that fascin, CD105, and Beta-catenin may be potential markers of aggressive breast cancer subtypes and predictors of recurrence and survival. These data also support pharmacological targets for these aggressive subtypes.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 692. doi:1538-7445.AM2012-692
Abstract 703: Verification of a novel approach to identify disease mechanisms in breast cancer patient subsets and application of this approach to indicating and characterizing tamoxifen resistance
Authors: Drubin David A. , Thomson Ty M. , Park Jennifer S. , Macoritto Michael , de Graaf David , Kenney Renee D.
Published: August 2012

Breast cancer is a heterogeneous disease that can be divided into distinct clinical and molecular subtypes. Key biomarkers such as the expression of HER2 or ER serve as a basis for subdividing the disease into distinct clinical entities and to distinguish patients who will most likely respond to specific targeted therapies, such as Herceptin and tamoxifen, respectively. Further understanding the molecular mechanistic differences among and within the breast cancer subtypes can facilitate the identification of treatment regimens that can be even more tailored to an individual's disease. If such a strategy is implemented, efficacy rates for cancer treatments can be improved, and more importantly, patients will be spared from any collateral effects of those treatments that will not combat their specific disease. We have taken a systems biology approach to segregate breast cancer patients into subgroups by semi-quantitatively evaluating the literature-derived molecular gene expression footprints of over 2100 mechanisms in our Knowledgebase. This approach effectively enables the stratification of breast cancer patients by their individual levels of signaling amplitude for these mechanisms. Using publicly available breast cancer data sets from GEO, we validated the stratification capability of these inferred mechanism activities against immunohistochemical staining for ER and HER2, and sequencing-based identification of TP53 mutation. In addition, applying this semi-quantitative evaluation of mechanism molecular footprints based on gene expression data from ER+ breast cancer patients before tamoxifen treatment (GSE17705), we developed a tamoxifen-sensitivity classifier a priori of knowledge of clinical outcome. This classifier enabled prediction of 16 of the 19 patients from an independent test set (GSE6532) who had gone on to develop distant metastases. Beyond identifying specific breast cancer sub-groups, which has been well established by clustering sets of genes, the systems biology-based approach presented here enables us to identify the specific mechanisms defining the separation of patient groups, and offers a means of either selecting the right patient population for a drug candidate or indicating additional/alternative disease pathways that could be targeted for clinical efficacy. This strategy is universal and can be applied to a variety of other cancers and diseases.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 703. doi:1538-7445.AM2012-703
Abstract 705: HER2 assessment to define outcomes for breast cancer patients treated with neoadjuvant therapy
Authors: Cheng Huan , Bai Yalai , Sikov Willliam , Sinclair Natalie , Abu-Khalaf Maysa , Harris Lyndsay N. , Rimm David L.
Published: August 2012

Background: HER2 expression or amplification is now an established companion diagnostic test. Now, as HER2-targeting neoadjuvant therapy for breast cancer increases, the accuracy of the companion diagnostic tests are revisited. Specifically, we seek to determine with the level of expression of the target (HER2 protein) is associated with pathologic response. In this study, we quantitatively assess HER2 expression both before and after the neoadjuvant therapies to breast cancer in the BrUOG BR-211B (NCT00617942) trial. Methods: We evaluated core biopsy samples from breast cancer patients enrolled in a preoperative clinical trial using trastuzumab, nab-paclitaxel and carboplatin combination therapy. Tumor core biopsies were taken before and after 10 days of either trastuzumab or nab-paclitaxel treatment. Combination chemotherapy was given for 6 cycles. Automated quantitative analysis (AQUA), a fluorescent-based method for analysis of in situ protein expression, was used to assess HER2 and phospho-HER2 expression in the BruOG Cohort, a study where patients who serially received Herceptin and Abraxane were biopsied both before and after treatment. This study assesses the HER2 positive patient subset (n=27) Results: Of 18 evaluable patients, the 8 with a PathCR showed a mean HER2 levels of 10251 compared with 4766 in the patients without PathCR (p=0.0047). This is notable in that a HER2 score of 2000 is equivalent to HER2 2+ in previous studies. Measurement of Phospho-HER2 showed no difference in PathCR vs Non-PathCR groups. A small subset (9) cases were measured for HER2 immediately after treatment, but the study has accrued an insufficient number of cases to statistically determine if there is a reduction in HER2 immediately following treatment. Conclusions: High levels of HER2 are associated with PathCR in the neoadjuvant setting. Levels of Phospho-HER2 are not associated with response. Further studies are underway to determine changes in levels of HER2 immediately after treatment.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 705. doi:1538-7445.AM2012-705
Abstract 716: High viral load is associated with poor postoperative survival in hepatitis B virus-related hepatocellular carcinoma
Authors: Yang Tian , Zhao Ronghua , Zhai Jian , Yu Wei-Feng , Yang Guang-Shun , Wu Meng-Chao , Lu Jun-Hua
Published: August 2012

Background & Aims: The aim of this prospective cohort study was to investigate the impact of preoperative hepatitis B viral load, as well as postoperative antiviral therapy, on the risk of long-term survival after curative resection of hepatitis B virus-related hepatocellular carcinoma (HCC). Methods A prospective cohort of hepatitis B virus-related HCC patients undergoing curative resection from 2001 to 2007 was studied. According to preoperative viral load (using 10,000 copies/mL of hepatitis B virus DNA level as cut-off value), two groups were compared. Prognostic factors for overall survival and recurrence-free survival were evaluated. Additionally, subgroup analysis was conducted in patients with high viral load to investigate prediction of postoperative antiviral therapy on the long-term prognosis. Results With a median follow-up of 49.1 months, patients with high viral load had lower median overall survival (78.3 months vs. 111.4 months, P < 0.001) and RFS (44.6 months vs. 94.8 months, P < 0.001) compared with those with low viral load. Multivariate analysis revealed that preoperative high viral load was an independent risk factor affecting both overall survival and recurrence-free survival (both P < 0.001). The subgroup analysis revealed that postoperative antiviral therapy independently improved recurrence-free survival for patients with high viral load (P = 0.001). Conclusions Hepatitis B virus-related HCC patients with preoperative high viral load led to poorer overall and recurrence-free survival than those with low viral load after curative resection. To prevent postoperative recurrence, antiviral therapy should be initiated in those patients with hepatitis B virus DNA ≤ 10,000 copies/ml.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 716. doi:1538-7445.AM2012-716
Abstract 718: microRNA-29a* is a predictor for early recurrence hepatitis B virus-related hepatocellular carcinoma after surgical resection
Authors: Zhu Hai-Tao , Dong Qiong-Zhu , Sheng Yuan-Yuan , Wei Jin-Wang , Wang Guan , Zhou Hai-Jun , Ren Ning , Jia Hu-Liang , Ye Qing-Hai , Qin Lun-Xiu
Published: August 2012

Purpose: Early tumor recurrence after liver resection for hepatocellular carcinoma (HCC) was mainly due to intrahepatic tumor spreading. In this study, we set out to identify specific microRNA (miRNA) which might be used in predicting the possibility of early recurrence after HCC resection. Experimental Design: Taqman low density arrays were used to detect the miRNA expression levels in both the microdissected tumorous and adjacent non-tumorous liver tissues from 20 HCC patients. Quantitative real-time PCR (qRT-PCR) was used to verify the findings in 106 patients, and to develop a predictive assay. The identified miRNAs were further validated in an independent cohort of 112 patients. Results: Thirty seven selected miRNAs were validated in 106 HCC patients using qRT-PCR. A significant association was found between miR-29a* level in HCC tissues and early recurrence (P=0.0002). This association was further confirmed in the independent testing set of 112 patients (P=0.0154), in which miR-29a* level was significantly associated with both time to tumor recurrence (TTR) (P=0.0015) and overall survival (OS) (P=0.0079) of patients. In the univariate and multivariate analyses, miR-29a* was identified as an independent factor for TTR, particularly for those patients with early stage of HCC. The sensitivity and specificity of miR-29a* for the prediction of early HCC recurrence in an independent blinded validation set reached 74.2% and 68.2%, respectively. Conclusion: MiR-29a* might be a useful marker for prediction of early recurrence of HCC, particularly for those with early stage of HCC.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 718. doi:1538-7445.AM2012-718
Abstract 72: Amino terminus of SEPT9_i1 impacts cellular localization: Implications for mammary tumorigenesis
Authors: Stanbery Laura , Petty Elizabeth M. , Merajver Sofia D.
Published: August 2012

Septins were first discovered in Saccharomyces cerevisiae as proteins essential for faithful cell division. They are highly conserved and found in all eukaryotes with the exception of plants. One septin, SEPT9, was cloned from a region of allelic imbalance in breast and ovarian cancers on chromosome 17q25. Further analysis showed that SEPT9 encoded multiple protein isoforms. Retroviral expression of one isoform, SEPT9_i1, promoted oncogenic phenotypes including, increased cell proliferation, invasion, motility, and genomic instability in mammary epithelial cells. In addition, abnormal nuclear localization of SEPT9_i1 was observed. SEPT9_i1 is highly expressed in many cancers including, breast, ovarian, prostate, and head and neck. SEPT9_i1 differs from other SEPT9 isoforms by 25 unique amino acids at the N terminus. SEPT9_i3, which lacks these 25 amino acids, does not exhibit the same pro-oncogenic phenotypes associated with SEPT9_i1. The goal of this study is to determine the functional relevance of these amino acids with respect to cellular localization as well as phenotypes related to mammary tumorigenesis and metastasis. First, bioinformatic analysis revealed a bipartite nuclear localization signal within the 25 unique amino acids but no other recognized functional domains. To determine the effects of these 25 amino acids on nuclear localization, FLAG-tagged deletion (ΔN)-SEPT9_i1, full-length (FL) -SEPT9_i1, and empty vector control constructs were transiently transfected into two immortalized human mammary epithelial cell lines, HME and MCF-10a. Immunofluorescence analyses of FL-SEPT9_i1 and ΔN-SEPT9_i1 localization revealed a dramatic decrease in the amount of SEPT9_i1 localized to the nucleus in the ΔN-SEPT9_i1 versus FL- SEPT9_i1 lines. Stably expressing FL-SEPT9_i1 and ΔN-SEPT9_i1 HS578t cell lines were also generated using nucleofection for examination of the effects of ΔN-SEPT9_i1 on cellular phenotypes including cell proliferation, cell motility and invasion. We present data indicating that the deletion of the N terminal 25 amino acids decreases cell motility and invasion as compared to SEPT9_i1 in HS578t cells. In addition, we show increased cell proliferation in cells expressing ΔN-SEPT9_i1 as compared to both EV and SEPT9_i1. To date our results implicate an oncogenic role for high SEPT9_i1 in mammary tumorigenesis where the unique 25 amino acids of SEPT9_i1 may impact tumorigenesis. Further investigation could provide valuable insight into developing targeted chemotherapeutic agents.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 72. doi:1538-7445.AM2012-72
Abstract 73: The transfection of high mobility group protein AT-hook 1 (HMGA1) is associated with the development of androgen independency in prostate cancer cells
Authors: Takaha Natsuki , Takeuchi Ichiro , Kimura Yasunori , Iwata Tsuyoshi , Nakamura Terukazu , Hongo Fumiya , Mikami Kazuya , Kamoi Kazumi , Okihara Koji , Kawauchi Akihiro , Miki Tsuneharu
Published: August 2012

The level of HMGA1 is low in androgen-dependent prostate cancer cell line (LNCaP), but is high in androgen-independent prostate cancer cell lines (DU145, PC-3). We have reported that the level of HMGA1 expression in prostate cancer cells is correlated with the extent of chromosomal aberrations (Can Res, 2002) and that transfection of HMGA1 into prostate cancer cell lines induces unbalanced chromosomal rearrangement and expression of matrix metalloproteinase 2 (Prostate, 2004). This suggests that HMGA1 is a strong candidate gene playing a potential role in the progression of prostate cancer. These findings have prompted us to evaluate the effect of HMGA1 on androgen independency, which is associated with the progression of prostate cancer. The androgen-dependent LNCaP cell line was induced to an androgen-independent subline (LN95) by being maintained for long term in the absence of androgen. The absence of androgen induced a 2.5-fold increase in the level of HMGA1 in the LN95 cell line. Androgen deprivation in vitro for 4 days as well as that for 8 days in vivo induced significant increase in the level of HMGA1 in parental LNCaP. On the other hand, the level of HMGA1 in normal prostate of mice 4 days and 11 days after castration as well as sham operation was almost undetectable. The cell proliferation rates of LNCaP cell transfected with HMGA1a vector (LN-H1) and LNCaP cell transfected with control empty vector (LN-EV) were determined with various concentrations (0-1nM) of dihydrotestosterone (DHT) by WST-8 assay in order to examine the effect of HMGA1 on androgen sensitivity. The expression of HMGA1 protein in LNH1 was confirmed to be 3.2-fold as high as that in LNEV. In low concentration (0-0.01 nM) of DHT, LNEV cell could not keep proliferation over day 6, while LNH1 could maintain proliferation over day 6. The cell proliferation rate at day 8 of LN-H1 grown in low concentration (0-0.01 nM) of DHT was about 2-fold higher than that of LN-EV. In contrast, both LN-H1 and LN-EV cells grew equally well in higher concentrations (0.1-1 nM) of DHT and could also keep proliferation over day6. Suppression of HMGA1 in DU145 and PC-3 by siRNA decreased cell proliferation rate and colony formation ability by 40% and 10-fold, respectively, in androgen-deprived medium. These data suggest that HMGA1 is associated with the transition of prostate cancer cells from androgen-sensitive to androgen-independent growth and plays a role in the cell growth of androgen-independent prostate cancer cells.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 73. doi:1538-7445.AM2012-73