[17] Tang J, Huang Y, Nguyen DH, Costes SV, Snijders AM, Mao JH. "Genetic background modulates lncRNA-modulated tissue response to low dose ionizing radiation." International Journal of Genomics February 2015, Provisional PDF [Link]

 

 

[16] Nguyen DH, Ouyang H, Mao JH, Hlatky L, and Barcellos-Hoff MH. "Distinct luminal type mammary carcinomas arise from orthotopic Trp53 null mammary transplantation of juvenile versus adult mice." Cancer Research 2014; Oct. 3, Published OnlineFirst [Link]

There are at least six different subtypes of breast cancer that are recognized in the clinic. The first fascinating feature of this paper is that breast cancers that develop during puberty in a mouse grow faster and are more highly positive for the estrogen receptor-alpha (ER) protein than tumors that develop in an adult mouse.  

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Researchers are searching for the genes that, when individually mutated in a breast cell, will result in one of the six breast cancer subtypes (the gene-centric perspective). The second fascinating feature of this paper is that it provides evidence that the luminal subtype of breast cancer (ER+, PR+, HER2+) can be enriched without direclty mutating a gene, but simply by allowing the cancer to develop in a pubertal mouse. This underscores the power of the host environment, otherwise known the physiological status, in determining clinically relevant aspects of a breast cancer (the microenvironment and host-environment perspective).  

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[15] Nguyen DH. "Thyroid inflammation associates with down-regulation of FOXE1 and enrichment for a stem cell transcriptome implicating epithelial dedifferentiation as a mechanism of thyroid cancer risk due to thyroiditis." Abstract reported at the 2nd World Congress on Thyroid Cancer, July 10-14, 2013 (Toronto, Canada). [Abstract Link: Scroll to bottom] [Manuscript in preparation]

Thyroiditis, or inflammation of the thyroid, is a risk factor for developing thyroid cancer later in life. FOXE1 is a gene for which a reduced functionality is associated with increased thyroid cancer risk. This study found that inflamed human thyroid tissues exhibit a down-regulation of FOXE1, which is accompanied by a de-differentiated transcriptome. This suggests that thyroid inflammation may increase the risk of thyroid cancer because the whole tissue undergoes a transcriptomic reversion, not obvious via histology, to a stem-like state. This entails that thyroiditis results in more stem-like targets that can undergo spontaneous or carcinogen-induced transformation. This may explain why common thyroiditis conditions (e.g. goiter) such as Grave's disease and Hashimoto's disease are associated with an increased risk for developing thyroid cancer. It also suggests that goiter is a window of susceptibility for thyroid cancer initiation, which is relevant for public health, environmental toxicology, and preventive medicine measures.

 

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[14] Tang J, Fernandez-Garcia I, Vijayakumar S, Martinez-Ruiz H, Illa-Bochaca I, Nguyen DH, Mao JH, Costes SV, Barcellos-Hoff MH. "Irradiation of juvenile, but not adult, mammary gland increases stem cell self-renewal and estrogen receptor negative tumors." Stem Cells 2013; Aug 23. [Link]

[13] Nguyen DH, Zhou T, Shu J, and Mao JH (2013). “Quantifying chromogen intensity in immunohistochemistry via reciprocal intensity.” Cancer InCytes 2(1):e. [Link]

DHN invented a simple technique to quantify the intensity of a chromogen stain in immunohistochemistry by measuring the "reciprocal intensity" of the stain in bright field microscopy. This technique has the ability to detect nuanced expression of proteins between treatment groups, and can potentially stratify previously published human tissue data sets into new cohorts with distinct prognoses or responses to therapy. The result would be increased potential for more specific treatment regimens, which would minimize adverse effects of over- or unnecessary treatment.

 

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[12] Nguyen DH, Fredlund E, Zhao W, Perou C, Balmain A, Mao JH, Barcellos-Hoff MH. (2013). Murine microenvironment metaprofiles associate with human cancer etiology and intrinsic subtypes. Clinical Cancer Research 19(6):1353-62. [Link]

This paper suggests that the transcriptome of mouse breast tumors from irradiated host mice (the tumors were never irradiated) have similar properties as human basal-like breast cancers. It also suggests that stem cell programs and inflammation may be mechanisms by which radiation-preceded cancers (in survivors of nuclear accidents) develop.

 

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[11] Lee DY, Bowen B, Nguyen DH, Parsa S, Huang Y, Mao JH, Northen T (2012). Low-dose ionizing radiation-induced blood plasma response in a diverse genetic mouse population. Radiation Research 178(6):551-5. [Link]

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[10] Nguyen DH, Zhou T, Shu J, Hua H, Mao JH. (2012). Two applications of a fluorescent chromogen in immunohistochemistry of formalin-fixed paraffin-embedded tissue sections to overcome common limitations of detection. Cancer InCytes 1(1):e. [Link]

This paper presents the idea that if a fluorescent chromogen can be nearly invisible under bright field microscopy, yet detectable under UV, then it could in principle be combined with hematoxylin & eosin stains to help pathologists better assess tissue structure (i.e. tumor grade). Many challenges remain before this becomes feasible, but this article attempts to start the conversation.

 

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[9] Nguyen DH. (2011). Stromal Modulation of Radiation Carcinogenesis in Breast Cancer." ProQuest/UMI (Ann Arbor) [Link]

Doctoral Disseration

Noteworthy: Chapter 3 provides preliminary evidence and proposes that the normal-like subtype of human breast cancer may originate from -- or at least share similarities with -- a mammary progenitor cell (pp. 63-73).

 

Chapter 2 was augmented and published in Cancer Cell [See 8]. Part of Chapter 3 was augmented and published in Clinical Cancer Research [See 12].

 

 

[8] Nguyen DH, Oketch-Rabah HA, Illa-Bochaca I, Geyer FC, Reis-Filho JS, Mao JH, Ravani SA, Zavadil J, Borowsky AD, Jerry DJ, Dunphy KA, Seo JH, Haslam S, Medina D, Barcellos-Hoff MH. (2011). Radiation Acts on the Microenvironment to Affect Breast Carcinogenesis by Distinct Mechanisms that Decrease Cancer Latency and Affect Tumor Type. Cancer Cell 19, 640-651. [Link]

The classical understanding of how radiation causes cancer is that it causes DNA damage. This paper is proof of principle that a low dose of radiation [10 cGy of ionizing radiation (dose to chest area after several CT scans)] can promote breast cancer without having to directly cause DNA damage in the epithelial cells that will eventually give rise to the tumor. 

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Irradiating the host (non-tumor cells) promotes the development of aggressive ER-alpha negative breast cancers, suggesting that the host environment significantly influences the selection of certain breast cancer molecular subtypes.  It is thought that mutations in genes, such as BRCA1 or PI3K, in epithelial cells are the main drivers of subtype selection, but this paper suggests that non-epithelial autonomous mechanisms in the host environment can significantly influence which subtype develops. 

 

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[7] Nguyen DH, Bochaca II, Barcellos-Hoff MH. (2011) "The Biological Impact of Radiation Exposure on Breast Cancer Development." The Environment and Breast Cancer. Jose Russo (ed.). Springer (New York). pp 185-203. [Link]

Risk of developing cancer after exposure to ionizing radiation is calculated based on the linear-no-threshold (LNT) model, which posits that the risk is directly proportional to dose. This linear relationship is extrapolated to very low doses [less than 10 cGy (the dose to the chest area after several CT scans)] even though epidemiological data for risk in this dose range is inconclusive. At doses below 10 cGy, we and others have reported "non-targeted effects" of ionizing radiation (as in, non-mutagenic effects), which can promote cancer but exhibit a non-linear threshold response.  Due to conventional adherence to the LNT model, it is difficult to incorporate non-targeted effects of low doses into risk assessments.  

DHN proposed that non-targeted effects can in principle be incorporated into the LNT model of risk if they are added as a weighting factor that affects conventional parameters. 

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[6] Nguyen DH, Martinez-Ruiz H, Barcellos-Hoff MH. (2011). Consequences of Epithelial or Stromal TGFbeta1 Depletion in the Mammary Gland. J Mammary Gland Biol Neoplasia 16, 147-155. [Link]

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[5] Barcellos-Hoff MH, Nguyen DH. (2009). Radiation carcinogenesis in context: how do irradiated tissues become tumors? Health Physics 97(5):446-57. [Link]

  

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[4] Nguyen HH, Lavrenov SN, Sundar SN, Nguyen DH, Tseng M, Marconett CN, Kung J, Staub RE, Preobrazhenskaya MN, Bjeldanes LF, Firestone GL (2010). 1-Benzyl-indole-3-carbinol is a novel indole-3-carbinol derivative with significantly enhanced potency of anti-proliferative and anti-estrogenic properties in human breast cancer cells. Chemical Biological Interactions 186(3):255-66.

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[3] Nguyen HH, Aronchik I, Brar GA, Nguyen DH, Bjeldanes LF, Firestone GL (2008). The dietary phytochemical indole-3-carbinol is a natural elastase enzymatic inhibitor that disrupts cyclin E protein processing. Proceedings of the National Academy of Sciences 105(50): 19750-5.

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[2] Costes SV, Ponomarev A, Chen JL, Nguyen D, Cucinotta FA, Barcellos-Hoff MH (2007). Image-based modeling reveals dynamic redistribution of DNA damage into nuclear sub-domains. PLoS Computational Biology (8): e155.

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[1] Garcia HH, Brar GA, Nguyen DH, Bjeldanes LF, Firestone GL (2005). Indole-3-carbinol (I3C) inhibits cyclin-dependent kinase-2 function in human breast cancer cells by regulating the size distribution, associated cyclin E forms, and subcellular localization of the CDK2 protein complex. Journal of Biological Chemistry 280(10): 8756-64. 

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