Shiuan Chen, Ph.D.

Breast Cancer Translation Research

Shiuan Chen, Ph.D., was one of the three investigators who originally isolated full-length human aromatase cDNA clones. He has a long-standing interest in the response of and resistance to hormone-directed therapies for breast cancer. The Chen laboratory characterized a collection of ER+ or AR+ PDX models (Kanaya, et al., 2016). Several projects have been developed using these PDX lines, including biomarker analysis of estrogen-stimulated and –suppressed ER+ PDXs, molecular characterization of AR+ triple-negative breast cancers, and drug responses of ER+/HER2+ cancers (Petrossian, et al., 2018; Yamamoto, et al., 2019; Kanaya, et al., 2019; Wang Y, et al., 2020; Wang Y, et al., 2020; Wang X, et al., 2021a; Wang X, et al., 2021b; Wang Y and Chen, 2021; Mori, et al., 2021).

Single cell RNA sequencing (scRNAseq) is a powerful technique that generates high resolution gene expression information at the individual cell level, allowing the characterization of heterogenous cell populations and complex cellular networks among different cell types. Such information cannot be obtained from bulk RNA sequencing.  In 2021, we published one single-cell paper linking mouse mammary gland development to breast carcinogenesis in woman (Saeki, et al., 2021). We generated a comprehensive mammary cell gene expression atlas with results from mouse mammary gland at most lifetime stages. The atlas was able to infer cells of origin of human breast cancer subtypes. As a nonbiased approach, we hypothesize that scRNAseq will be very useful to determine cellular features of ER+ and ER- cells in luminal cancers and possible gene expression changes/interaction among these cells under estrogen manipulation. For the first time, our single cell analysis (Mori, et al., 2021) has revealed that estrogen affects ESR1- cells in ER+ breast cancer, explaining why a 100% ER positivity is not required for an endocrine response. In a recent publication by Yoshitake, et al. (2022), we characterized mouse mammary fibroblasts with distinct functions, estrogen responses, differentiation processes, and crosstalks with epithelium. 

Spatial transcriptomics is a novel approach to spatially-resolve whole transcriptome mRNA expression, while capturing histological information in the same tissue section. Such a study will provide a comprehensive view of tissue complexity by mapping where all gene activity is occurring and discover novel targets with unbiased analyses. We have initiated a project to define different functions of cell clusters in ER+ breast cancer.

Lisa Yee, M.D., and Dr. Chen have initiated a new Phase 1 trial on the effect of mushroom on breast cancer prevention in high-risk women (NCT04913064). 
 

Prostate Cancer Translation Research

Dr. Chen has an extensive interest in the development of natural products as alternatives to and in conjunction with conventional Western medicines, including the potential role of plant-derived phytochemicals in prostate cancer prevention, risk of recurrence, and therapy. Based on earlier work in his laboratory, Dr. Chen, Przemyslaw Twardowski, M.D., Paul Frankel, Ph.D., Timothy Synold, Pharm.D., and Sumanta Pal, M.D., conducted a Phase 1 trial of white button mushroom (WBM) powder in patients with biochemically recurrent prostate cancer, examining the effects of WBM powder on serum PSA levels and determined the tolerability and biological activity of WBM (NCT00779168). Two patients experienced complete responses (CR; decline in PSA to undetectable levels) and two patients experienced partial responses (PR). Patients with CR and PR demonstrated higher levels of baseline interleukin-15 than non-responders, and this group had therapy-associated declines in myeloid-derived suppressor cells (MDSCs) (Twardowski, et al., 2015). A reverse translational research is initiated to examine the effect of mushroom intake on MDSC levels in mice.  With a grant from NIH in 2019 (R01 CA227230), the team (Chen, Twardowski, Lau, Frankel, and Synold) has started a Phase 2 trial to verify the finding from the first trial. We have received the approval of IND (from FDA) and IRB. The phase 2 trial was initiated in May 2021 (NCT04519879). Recently, we have published one paper to explain the anti-AR activity of mushroom chemicals (Wang X, et al., 2021a).

A proof-of-concept preclinical study has been completed to demonstrate that mushroom intake may slow down the COVID-19 infection through immune modulation. A paper to report these findings was published (Wang X, et al., 2021b).

Endocrine Disruptor Research

Our group is evaluating the impact of endocrine disrupting chemicals (EDCs) on the risk of breast cancer. EDCs may promote the development of breast cancer by interacting with aromatase (i.e. estrogen synthetase), estrogen receptor-α (ERα), estrogen receptor-β (ERβ), and/or progesterone receptor (PR). As EDC exposure events typically involve complex mixtures, Dr. Chen has developed a functional assay to determine the overall estrogenic and anti-aromatase activity of serum samples, the AroER tri-screen (Kanaya, et al., 2015). This high throughput screening system not only bypasses the need for single chemical measurements but also circumvents difficulties with isolating and defining post-exposure interactions between the EDCs and endogenous steroid hormones through conventional approaches. The screen has been used to identify potential aromatase inhibitors (AIs) in the U.S. Tox21 10K compound library (Chen, S. et al., 2015); ten AI-like compounds were identified, including the irreversible, long-lasting and potent anti-aromatase activity of imazalil, a fungicide widely used in agriculture. Such findings suggest that AroER tri-screen can screen and quantify unexpected or uncharacterized exposures to chemicals that interact with aromatase, ER, and PR during breast cancer development (Kanaya, et al., 2019; Bahrami, 2020). A collaboration between Dr. Chen and Lisa Yee, M.D., has been initiated to investigate the effects of aromatase inhibitor and natural product intake in high risk (for breast cancer) women by examining the changes of estrogen/androgen levels through AroER tri-screen assay. 

Dr. Chen and Susan Neuhausen, Ph.D., The Morris & Horowitz Families Professor in Cancer Etiology & Outcomes Research,  have investigated the impact of exposure to EDCs on the risk of breast cancer development during an important period of susceptibility, the menopausal transition. According to the Women’s Health Initiative (WHI), hormone therapy during this period increased both the incidence of and mortality from breast cancer. To investigate whether EDCs mimic this therapy and also promote the development of breast cancer during the menopausal transition, the team has interrogated two EDCs that have been recognized as major health concerns: polybrominated diphenyl ethers (PBDEs) and bisphenol A (BPA), a commonly used component in food-grade plastics. A transdisciplinary approach included cell culture, mouse models, and samples collected from women during the menopausal transition. The approach involved our AroER-Tri screen to interrogate EDC mechanisms; determined the effects of EDCs in women during menopausal transition on the estrogenic activity and the epigenome; and tested the effects of EDCs on the development of mammary lesions in a mouse model of menopause. In addition, with their community partners, the team has also provided a web-based resource on the role of exposures on development of breast cancer. 

We have studied the combined action of estrogen and polybrominated diphenyl ethers (PBDEs) in mammary gland through scRNAseq approach (Kanaya, et al., 2019) and reviewed the importance of this technique in the field of environmental carcinogenesis (Chang, et al., 2020).  

Information listed here is obtained from PubMed, a public database. City of Hope is not responsible for its accuracy. Selected Peer-reviewed Publications (Selected from 266 peer reviewed publications)

Yoshitake R, Chang G, Saeki K, Ha D, Wu X, Wang J, Chen S. Single-cell transcriptomics identifies heterogeneity of mouse mammary gland fibroblasts with distinct functions, estrogen responses, differentiation processes, and crosstalks with epithelium. Frontiers in Cell and Developmental Biology, 10: 850568, 2022. PubMed PMID: 35300413; PubMed Central PMCID: PMC8923650

Mori H, Saeki K, Chang G, Wang J, Wu X, Hsu PY, Kanaya N, Wang X, Somlo G, Nakamura M, Bild A, Chen S. Influence of estrogen treatment on ESR1+ and ESR1- cells in ER+ breast cancer: Insights from single-cell analysis of patient-derived xenograft models. Cancers (Basel), 13 (24): 6375, 2021. PubMed PMID: 34944995; PubMed Central PMCID: PMC8699443

Wang Y, Chen S. TXNIP links anticipatory unfolded protein responses to estrogen reprogramming glucose metabolism in breast cancer cells. Endocrinology, 163 (1): bqab212, 2022. PubMed PMID: 34614512 

Wang SF, Chang YL, Tzeng YD, Wu CL, Wang YZ, Tseng LM, Chen S, Lee HC. Mitochondrial stress adaptation promotes resistance to aromatase inhibitor in human breast cancer cells via ROS/calcium up-regulated amphiregulin-estrogen receptor loop signaling. Cancer Lett. 523: 82-99, 2021. PubMed PMID: 34610415

Augusto TV, Amaral C, Wang Y, Chen S, Almeida CF, Teixeira N, Correia-da-Silva G. Effects of PI3K inhibition in AI-resistant breast cancer cell lines: autophagy, apoptosis, and cell cycle progression. Breast Cancer Res Treat. 190(2): 227-240, 2021. PubMed PMID: 34498152
 
Wang X, Ha D, Yoshitake R, Chan YS, Sadava D, Chen S. Exploring the biological activity and mechanism of xenoestrogens and phytoestrogens in cancers: Emerging methods and concepts. Int J Mol Sci. 22(16): 8798, 2021. PubMed PMID: 34445499; PubMed Central PMCID: PMC8395949
 
Ding YC, Hurley S, Park JS, Steele L, Rakoff M, Zhu Y, Zhao J, LaBarge M, Bernstein L, Chen S, Reyolds P, Neuhausen SL. Methylation biomarkers of polybrominated diphenyl ethers (PBDEs) and association with breast cancer risk at the time of menopause. Environ Int. 156: 106772, 2021. PubMed PMID: 344425644
 
Wang X, Ha D, Yoshitake R, Chen S. White button mushroom interrupts tissue AR-mediated TMPRSS2 expression and attenuates pro-inflammatory cytokines in C57BL/6 mice. NPJ Sci Food. 5(1): 20, 2021. PubMed PMID: 34341347; PubMed Central PMCID: PMC8329194
 
Saeki K, Chang G, Kanaya N, Wu X, Wang J, Bernal L, Ha D, Neuhausen S, Chen S. Mammary cell gene expression atlas links epithelial cell remodeling events to breast carcinogenesis. Commun Biol. 4(1): 892, 2021. PubMed PMID: 34079055; PubMed Central PMCID: PMC8172904
 
Saghaeidehkordi A, Chen S, Yang S, Kuar K. Evaluation of a keratin 1 targeting peptide-doxorubicin conjugate in a mouse model of triple-negative breast cancer. Pharmaceutics, 13(5): 661, 2021. PubMed PMID: 34063098; PubMed Central PMCID: PMC8148172 

Rooney J, Ryan N, Liu J, Houtman R, van Beuningen R, Hsieh J, Chang G, Chen S, Corton C. A Gene Expression Biomarker Identifies Chemical Modulators of Estrogen Receptor ɑ in an MCF-⁊ Microarray Compendium. Chem Res Toxicol. 34(2):313-329, 2021. PubMed PMID: 33405908 

Wang X, Ha D, Mori H, Chen S. White button mushroom (Agaricus bisporus) disrupts androgen receptor signaling in human prostate cancer cells and patient-derived xenograft. J Nutr Biochem. 89:108580, 2021. PubMed PMID: 33388344; PubMed Central PMCID: PMC8542389 

Barnard L, Schiffer L, Louw du-Toit R, Tamblyn J, Chen S, Africander D, Arlt W, Foster P, Storbeck K. 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool. Endocrinology. 162(3): bqaa231, 2021. PubMed PMID: 33340399; PubMed Central PMCID: PMC7814299

Wang X, Petrossian K, Huang M, Saeki K, Kanaya N, Chang G, Somlo G, Chen S. Functional characterization of androgen receptor in two patient-derived xenograft models of triple negative breast cancer. J Steroid Biochem Mol Biol. 206: 105791, 2021. PubMed PMID: 33271252; PubMed Central PMCID: PMC8820229 

Wang Y, Tzeng Y, Chang G, Wang X, Chen S. Amphiregulin retains ERɑ expression in acquired aromatase inhibitor resistant breast cancer cells. Endocr Relat Cancer. doi:10.1530/ERC-20-0258. 2020. PubMed PMID: 33112819; PubMed Central PMCID: PMC7665895 

Wang S, Chen S, Tseng L, Lee H. Role of the mitochondrial stress response in human cancer progression. Exp Biol Med (Maywood). doi: 10.1177/1535370220920558. Epub 2020. PubMed PMID: 32326760; PubMed Central PMCID: PMC7268930 

Bahrami N, Chang G, Kanaya N, Sauer T, Park D, Loeng M, Gravdehaug B, Chen S, Geisler J. Changes in serum estrogenic activity during neoadjuvant therapy with letrozole and exemestane. J Steroid Biochem Mol Biol. doi: 10.1016/j.jsbmb.2020.105641. Epub 2020. PubMed PMID: 32151708

Chang G, Saeki K, Mori H, Chen S. Environmental Carcinogenesis at the Single Cell Level. Cancer Epidemiol Biomarkers & Prevention. pii: cebp.1364.2019. doi: 10.1158/1055-9965.EPI-19-1364. [Epub ahead of print] 2020. PubMed PMID: 32132147; PubMed Central PMCID: PMC7483229 

Ziaei E, Saghaeidehkordi A, Dill C, Maslennikov I, Chen S, Kuar K. Targeting triple negative breast cancer cells with novel cytotoxic peptide-doxorubicin conjugates. Bioconjug Chem. 30 (12): 3098-3106, 2019. PubMed PMID: 31715102; PubMed Central PMCID: PMC7965737 

Kanaya N, Chang G, Wu X, Saeki K, Bernal L, Shim HJ, Wang J, Warden C, Yamamoto T, Li J, Park JS, Synold T, Vonderfecht S, Rakoff M, Neuhausen SL, Chen S. Single-cell RNA-sequencing analysis of estrogen- and endocrine-disrupting chemical-induced reorganization of mouse mammary gland. Commun Biol. 2019 Nov 5; 2: 406. Doi: 10. 1038/s42003-019-0618-9. eCollection 2019. PubMed PMID: 31701034; PubMed Central PMCID: PMC6831695 

Zhang S, Sugawara Y, Chen S, Beelman RB, Tsuduki T, Tomata Y, Matsuyama S, Tsuji I. Mushroom consumption and incident risk of prostate cancer in Japan: A pooled analysis of the Miyagi Cohort Study and the Ohsaki Cohort Study. Int J Cancer. 2019 Sep. 4. Doi: 10.1002/ijc.32591 [Epub ahead of print]. 2019. PubMed PMID: 31486077; PubMed Central PMCID: PMC7154543 

Terry MB, Michels KB, Brody JG, Byrne C, Chen S, Jerry DJ, Malecki KMC, Martin MB, Miller RL, Neuhausen SL, Silk K, Trentham-Dietz A. Breast Cancer and the Environment Research Program (BCERP). Environmental exposures during windows of susceptibility for breast cancer: a framework for prevention research. Breast Cancer Res. 21 (1): 96 doi: 10.1186/s13058-019-1168-2, 2019. PubMed PMID: 31429809; PubMed Central PMCID: PMC6701090 

Kanaya N, Bernal L, Chang G, Yamamoto T, Nguyen D, Wang YZ, Park JS, Warden C, Wang J, Wu X, Synold T, Rakoff M, Neuhausen SL, Chen S. Molecular mechanisms of polybrominated diphenyl ethers (BDE-47, -100, -153) in human breast cancer cells and patient-derived xenografts. Toxicol Sci, 169 (2): 380-398, 2019. PubMed PMID: 30796839; PubMed Central PMCID: PMC6542340 

Yamamoto T, Kanaya N, Somlo G, Chen S. Synergistic anti-cancer activity of CDK4/6 inhibitor palbociclib and dual mTOR kinase inhibitor MLN0128 in pRb-expressing ER-negative breast cancer. Breast Cancer Res Treat, Jan 3 doi: 10. 1007/s 10549-018-05104-9. [Epub ahead of print], 2019. PubMed PMID: 30607633; PubMed Central PMCID: PMC6452902 

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