Department of Cancer Biology

Saori Furuta, Ph.D.

saori furuta Saori Furuta, Ph.D.
Assistant Professor  
Cancer Biology


Over 300,000 new cases of breast cancer are diagnosed in the U.S. each year, affecting 1 in 8 women in their lifetime. Despite the recent advances in diagnostic tools, breast cancer mortality rate has only declined slowly, justifying the urgent need for a better diagnostic marker and treatment modality.

The long-term goal of our research is to determine the specific roles of tissue microenvironment in regulating homeostasis vs. precancerous progression of the breast as well as therapeutic resistance. In particular, we are investigating how disrupted nitroso-redox balance influences different components of tissue microenvironment (e.g., extracellular matrix (ECM), fibroblasts, macrophages and secreted cytokines) and contributes to cancer initiation/progression and therapeutic resistance.

Fig. 1. Normal vs. malignant breast tissues staining for S-nitrosocysteine, the marker for nitric oxide.

There are four on-going relevant projects in the laboratory:

1.  Determine how deficiency of nitric oxide upregulates HER2 and TGFß and induces precancerous lesions in mammary glands.

We previously found that the level of nitric oxide (NO) plummets during breast cancer progression in parallel to reduction of tetrahydrobiopterin (BH4, the essential cofactor of NO synthase). Pharmacological deprivation of NO in wild-type animals induced desmoplastic fibrous ECM and precancerous mammary lesions that overexpressed HER2 and TGFß. On the other hand, restoration of the basal NO level in panel of breast cancer cell lines with sepiapterin (the precursor of BH4) suppressed their growth by inhibiting the expression of HER2 and TGFß. We hypothesize that NO helps suppress the expression of HER2 and TGFß through S-nitrosylation (SNO, NO-mediated modification of certain cysteines), whereas NO deficiency deprives SNO, unleashing these two tumorigenic proteins (Fig. 2). The current project is first to identify the SNO sites in HER2 and TGFß, as well as their upstream regulators, and the pathogenic relevance of defective SNO to precancerous progression of the breast. Then, we will test the utility of SNO of these proteins as biomarkers in precancerous human tissues.

                                                                Fig. 2. Working model for SNO-mediated suppression
                                                                of the expression of HER2 and TGFß and HER2 in 
                                                                normal breast cells.

2.  Determine the therapeutic efficacy of sepiapterin (the precursor of BH4, the essential cofactor of NO synthase) in suppressing the growth of HER2-positive mammary tumors in animals.

We previously found that reduction of NO during breast cancer progression was correlated to the dramatic decrease of tetrahydrobiopterin (BH4), the redox-sensitive, essential cofactor of NO synthase (NOS), under increased oxidative stress. We then administered sepiapterin, the precursor of BH4, to a panel of different breast cell lines in 3D ECM cultures and found that sepiapterin treatment led to a dramatic decline (60-90%) of proliferation of cancer cells without affecting normal cells. The current project is to test whether sepiapterin (alone or in combination with anti-angiogenic drugs) could ameliorate the growth of HER2-positive mammary tumors in animals.
                                                            Fig. 3. Working model for M1-to-M2 conversion of 
                                                            macrophages by sepiapterin, the precursor of BH4,
                                                            the essential cofactor of NO synthase.
3.  Determine whether sepiapterin could reprogram M2 to M1 macrophages, improving the immunotherapy for breast cancer.

Previous studies showed that BH4 level is differentially modulated during macrophage polarization because of differential levels of GCH1, the rate-limiting enzyme of de novo biosynthesis of BH4. BH4 levels become extremely high during M1 polarization, whereas it becomes almost undetectable during M2 polarization. We hypothesize that administration of sepiapterin, an intermediate of the salvage pathway of BH4, to M2 macrophage will induce reprogramming of M2 to M1 macrophages (Fig. 3). Our preliminary results showed that administration of sepiapterin to M2-polarized THP-1 cells induced their conversion to M1 type in culture. The current project is to test whether this phenomenon could be observed in M2-polarized primary macrophages in culture and in mice bearing HER2-positive mammary tumors.

4.  Generate and determine the efficacy of liposomes-based delivery system of sepiapterin that specifically targets HER2-positive cancer cells.

We previously found that sepiapterin treatment conferred strong (60~90%) growth suppression of different breast cancer cells in culture even after 2 hours of treatment. On the contrary, previous studies by another group showed that systemic administration of sepiapterin in animals suppressed the growth of HER2-positive mammary tumors by as much as 20%. Because the same group also reported that sepiapterin conferred strong angiogenetic stimuli to tumor vasculature, this might have dampened the anti-tumor effect of the drug. While testing the anti-tumor effect of the combinatorial treatment of sepiapterin and anti-angiogenic drugs (project #2 above), we are also generating liposomes that specifically deliver sepiapterin to HER2-positive cancer cells. The liposomes enclose sepiapterin and are loaded with HER2-binding peptide (Herceptin analog) and fluorophores excited at near-infrared wavelength to generate fluorescence as well as heat (photothermal therapy) (Fig. 4). We will test the efficacy of drug-delivery, stability and anti-tumor activities of liposomes using mice bearing HER2-positive mammary tumors. We hypothesize that this liposome-based drug delivery, combined with photothermal therapy, will specifically target and effectively kill HER2-positive mammary tumors.
                                                                 Fig. 4. HER2-targeting liposome loaded with
                                                                 near-infrared fluorophore and sepiapterin.

To implement these projects, we utilize a high-resolution image technique, including second harmonics generation on multiphoton microscope, time-lapse confocal microscopy and atomic force microscopy, as well as animal studies, mass spectrometry, 3D cultures (mono and co-cultures), histological studies of clinical samples and other molecular/cell biology/biochemistry techniques.

Dr. Furuta is a member of the faculty in the Biomedical Sciences Graduate Program, Cancer Biology track.

Postdoc 2007-2014, Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA
Ph.D. 2007, University of California, Irvine
M.S. 2001, California State University, Los Angeles
B.S. 1999, University of California, Riverside


2015-present Assistant Professor, Dept. Cancer Biology, University of Toledo College of Medicine & Life Sciences, Toledo, OH
2015-present Affiliate, Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA
2014-2015     Project Scientist, Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA


Makmura, L., Hamann, M., Areopagita, A., Furuta, S., Munoz, A., Momand, J. Development of sensitive assay to detect reversibly oxidized protein cysteine sulfhydryl groups. Antioxid. Redox Signal 2001; 3(6):1105-18.  PMID:  11813984

Furuta, S., Ortiz, F., Zhu, Sun X., Wu, HH., Mason, A., Momand, J. Copper uptake is required for pyrrolidine dithiocarbamate-mediated oxidation and protein level increase of p53 in cells. Biochem. J. 2002; 365(Pt 3):639-48.  PMC1222712

Utomo, A., Jiang, X., Furuta, S., (first three contributed equally) Yun, J., Levin, D.S., Wang,Y.C., Desai, K.V., Green, J.E., Chen, P.L., Lee, W.H. Identification of a novel putative non-selenocysteine containing phospholipid hydroperoxide glutathione peroxidase (NPGPx) essential for alleviating oxidative stress generated from polyunsaturated fatty acids in breast cancer cells. J Biol Chem. 2004; 279(42):43522-9.  PMID: 15294905

Furuta, S., Jiang, X., Gu, B, Cheng, E., Chen, P.L., Lee, W.H. Depletion of BRCA1 impairs differentiation but enhances proliferation of mammary epithelial cells. Proc Natl Acad Sci U S A. 2005; 102(26):9176-81.  PMC1166629

Momand, J., Aspuria, P.J., Furuta, S. “MDM2 and MDMX-regulators of p53 activity”, a chapter in Protein Reviews Vol 2: The p53 Tumor Suppressor Pathway and Cancer 2005; pp155-186. Kluwer Academic/Plenum Publishers (New York, NY).

Furuta, S., Wang, J., Shuanzeng, W., Jeng, Y.M., Jiang, X., Gu, B., Chen, P.L., Lee, E.Y.H.P., Lee, W.H. Removal of BRCA1/CtIP/ZBRK1 repressor complex on ANG1 promoter leads to accelerated breast tumor growth contributed by prominent vasculature. Cancer Cell 2006; 10(11):13-24.  PMID: 16843262

Jeng, Y.M., Cai, S., Li, A., Furuta, S., Chen, P.L., Lee, E.Y.H.P., Lee, W.H.  Brca1 heterozygous mice have shortened life span and are prone to ovarian tumorigenesis with haploinsufficiency upon ionizing irradiation. Oncogene 2007; 24(42):6160-6.  PMID: 17420720

Furuta, S., Jeng, Y.M., Zhou, L., Huang, L., Kuhn, I., Bissell, M.J., Lee, W.H.  IL-25 causes apoptosis of IL-25R-expressing breast cancer cells without toxicity to nonmalignant cells. Sci Transl Med. 2011; 3(78):78ra31.  PMC3199022

Furuta, S., Ghajar, C.M., Bissell, M.J. Caveolin-1: Would-be Achilles’ heel of tumor microenvironment? Cell Cycle 2011; 10:1794-1809.  PMID: 22030625

Ordinario, E., Han, H.J., Furuta, S., Heiser, L., Jakkula, L., Rodier, F., Spellman, P., Campisi, J., Gray, J., Bissell, M.J., Kohwi, Y., Kohwi-Shigematsu, T.  ATM suppresses SATB1-induced malignant progression in breast epithelial cells. PLOS One 2012;7(12):e51786.  PMC3519734

Lee, S-Y., Meier, R., Furuta, S. (first three contributed equally; SF serves as a co-corresponding author with MJB), Lenburg, M.E., Kenny, P.A.,  Xu, R.,  Bissell, M.J.  FAM83A confers EGFR-TKI resistance in breast cancer cells and in mice. J. Clin. Invest. 2012; 122(9):3211-3220.  PMC3428077

Becker-Weimann, S., Xiong, G., Furuta, S., Han, J., Kuhn, I., Akavia, U.D., Pe’er, D., Bissell, M.J., Xu, R. NF-kappaB integrates microenvironmental signals that disrupt tissue polarity and induce cell invasion in breast cancer cells. Oncotarget 2013; 4(11):2010-2010.  PMC3875766

Furuta, S., Bissell, M.J. (2016) Pathways involved in dormation of mammary organoid architecture have keys to understanding drug resistance and to discovery of druggable targets. Cold Spring Harb Symp Quant Biol., 2016; 81:207-217.  PMID: 28416576

Furuta, S.*, Ren, G., Mao, J.H., Bissell, M.J., Laminin signals initiate the receiprocal loop that informs breast-specific gene expression and homeostasis by activating NO, p53 and microRNAs. eLife 2018; 7:e26148. PMCID: PMC5862529.
(*SF also serves as a co-corresponding author with MJB)

Ricca, B.L., Venugopalan, G., Furuta, S., Tanner, K., Orellana, W.A., Reber, C.D., Brownfield, D.G., Bissell, M.J., Fletcher, D.A. Transient external force induces phenotypic reversion of malignant epithelial structures via nitric oxide signaling. eLife 2018; 7:e26161. PMCID: PMC5862525.

Ren, G., Zheng, X., Bommarito, M., Metzger, S., Letson, J., Walia, Y., Furuta, S. Reduced basal nitric oxide production induces precancerous mammary lesions via ERBB2 and TGFß. Sci. Rep., in revision.


Last Updated: 1/20/21