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).