The ability of a cancer cell to develop resistance to anoikis, a programmed cell death process triggered by substratum detachment, is a critical step in the metastatic cascade. Triple-negative breast cancers (TNBC) exhibit higher rates of metastasis after diagnosis, relative to estrogen-positive breast cancers, but while TNBC cells are relatively more resistant to anoikis, the mechanisms involved are unclear. Through gene expression and metabolomic profiling of TNBC cells in forced suspension culture, we identified a molecular pathway critical for anchorage-independent cell survival. TNBC cells in suspension upregulated multiple genes in the kynurenine pathway of tryptophan catabolism, including the enzyme tryptophan 2,3-dioxygenase (TDO2), in an NF-κB-dependent manner. Kynurenine production mediated by TDO2 in TNBC cells was sufficient to activate aryl hydrocarbon receptor (AhR), an endogenous kynurenine receptor. Notably, pharmacologic inhibition or genetic attenuation of TDO2 or AhR increased cellular sensitivity to anoikis, and also reduced proliferation, migration, and invasion of TNBC cells. In vivo, TDO2 inhibitor-treated TNBC cells inhibited colonization of the lung, suggesting that TDO2 enhanced metastatic capacity. In clinical specimens of TNBC, elevated expression of TDO2 was associated with increased disease grade, estrogen receptor-negative status, and shorter overall survival. Our results define an NF-κB-regulated signaling axis that promotes anoikis resistance, suggest functional connections with inflammatory modulation by the kynurenine pathway, and highlight TDO2 as an attractive target for treatment of this aggressive breast cancer subtype.

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A TDO2-AhR signaling axis facilitates anoikis resistance and metastasis in triple-negative breast cancer.

OBJECTIVE: To evaluate the evidence of the supplements vitamin C and vitamin E for treatment and prevention of cancer.

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Antioxidants vitamin C and vitamin e for the prevention and treatment of cancer.

Background: Antioxidants may protect normal cells from the oxidative damage that occurs during radiotherapy and certain chemotherapy regimens, however, the same mechanism could protect tumor cells and potentially reduce effectiveness of cancer treatments. We evaluated the association of vitamin supplement use in the first six-months after breast cancer diagnosis and during cancer treatment with total mortality and recurrence Methods: We conducted a population-based prospective cohort study of 4,877 women aged 20-75 years diagnosed with invasive breast cancer in Shanghai, China between March 2002 and April 2006. Women were interviewed approximately six-months after diagnosis and followed-up by in-person interviews and record linkage with the vital statistics registry. Results: During a mean follow-up of 4.1 years, 444 deaths and 532 recurrences occurred. Vitamin use shortly after breast cancer diagnosis was associated with reduced mortality and recurrence risk, adjusted for multiple lifestyle factors, sociodemographics, and known clinical prognostic factors. Women who used antioxidants (vitamin E, vitamin C, multivitamins) had 18% reduced mortality risk (hazard ratio (HR) = 0.82, 95% confidence interval (CI): 0.65-1.02) and 22% reduced recurrence risk (HR = 0.78, 95% CI: 0.63-0.95). The inverse association was found regardless of whether vitamin use was concurrent or non-concurrent with chemotherapy, but was only present among patients who did not receive radiotherapy. Conclusions: Vitamin supplement use in the first six months after breast cancer diagnosis may be associated with reduced risk of mortality and recurrence. Impact: Our results do not support the current recommendation that breast cancer patients should avoid use of vitamin supplements.

https://cebp.aacrjournals.org/content/cebp/20/2/262.full.pdf

Vitamin Supplement Use During Breast Cancer Treatment and Survival: A Prospective Cohort Study

Motivation: For the early detection of cancer, highly sensitive and specific biomarkers are needed. Particularly, biomarkers in bio-fluids are relatively more useful because those can be used for non-biopsy tests. Although the altered metabolic activities of cancer cells have been observed in many studies, little is known about metabolic biomarkers for cancer screening. In this study, a systematic method is proposed for identifying metabolic biomarkers in urine samples by selecting candidate biomarkers from altered genome-wide gene expression signatures of cancer cells. Biomarkers identified by the present study have increased coherence and robustness because the significances of biomarkers are validated in both gene expression profiles and metabolic profiles.

Results: The proposed method was applied to the gene expression profiles and urine samples of 50 breast cancer patients and 50 normal persons. Nine altered metabolic pathways were identified from the breast cancer gene expression signatures. Among these altered metabolic pathways, four metabolic biomarkers (Homovanillate, 4-hydroxyphenylacetate, 5-hydroxyindoleacetate and urea) were identified to be different in cancer and normal subjects (p <0.05). In the case of the predictive performance, the identified biomarkers achieved area under the ROC curve values of 0.75, 0.79 and 0.79, according to a linear discriminate analysis, a random forest classifier and on a support vector machine, respectively. Finally, biomarkers which showed consistent significance in pathways' gene expression as well as urine samples were identified.

Contact: dhlee@biosoft.kaist.ac.kr

Supplementary information: Supplementary data are available at Bioinformatics online.

Combining tissue transcriptomics and urine metabolomics for breast cancer biomarker identification

Purpose An estimated 45–80% of breast cancer patients use antioxidant supplements after diagnosis, and use of antioxidant supplements during breast cancer treatment is common. Dietary supplements with antioxidant effects include vitamins, minerals, phytonutrients, and other natural products. We conducted a comprehensive review of literature on the associations between antioxidant supplement use during breast cancer treatment and patient outcomes. Methods Inclusion criteria were: two or more subjects; clinical trial or observational study design; use of antioxidant supplements (vitamin C, vitamin E, antioxidant combinations, multivitamins, glutamine, glutathione, melatonin, or soy isoflavones) during chemotherapy, radiation therapy, and/or hormonal therapy for breast cancer as exposures; treatment toxicities, tumor response, recurrence, or survival as outcomes. Results We identified 22 articles that met those criteria. Their findings did not support any conclusions regarding the effects of individual antioxidant supplements during conventional breast cancer treatment on toxicities, tumor response, recurrence, or survival. A few studies suggested that antioxidant supplements might decrease side effects associated with treatment, including vitamin E for hot flashes due to hormonal therapy and glutamine for oral mucositis during chemotherapy. Underpowered trials suggest that melatonin may enhance tumor response during treatment. Conclusion The evidence is currently insufficient to inform clinician and patient guidelines on the use of antioxidant supplements during breast cancer treatment. Thus, well designed clinical trials and observational studies are needed to determine the short- and long-term effects of such agents.

Use of antioxidant supplements during breast cancer treatment: a comprehensive review.

The effect of long term ascorbic acid (AA) supplementation (3g per day) on 27 women with early breast cancer has been investigated For comparison a similar but limited study was carried out in patients with benign breast disease The responses of leucocyte levels of AA to supplementation provided some evidence to suggest that the metabolism and utilisation of the vitamin may be different in these patients In addition longitudinal measurements of urinary hydroxyproline/creatinine (OHPro/Cr) ratio were carried out in these patients The long term ingestion of AA did not appear to affect the prognosis of the disease in the early breast cancer group Similar 5 year survival rates were seen in the unsupplemented and supplemented cancer groups

Ascorbic acid supplementation and five year survival rates in women with early breast cancer.

Plasma levels of total tryptophan were significantly lower in 51 patients with breast cancer than in 14 women with benign breast cancer following surgery and after 12 weeks. The urinary excretion of xanthurenic and 5-hydroxyindoleacetic acids were similar in patients with cancer and benign disease but the excretion of N'-methylnicotinamide (NMN) was significantly higher (P less than 0.001) in the cancer patients. It is suggested that the elevated urinary excretions of NMN is due to higher NAD activity reflecting elevated glycolysis through the Cori cycle.

Dickerson Jw

Papers

Ascorbic acid supplementation and five year survival rates in women with early breast cancer.

Tryptophan metabolism in patients with breast cancer.