Research

Using genomic, proteomic and metabolomic approaches, these projects focus on the identification of therapeutic compounds that are both more effective and less toxic for the treatment of ER-negative, PR-negative and HER2-negative (or “triple-negative”) breast cancers.

One of the goals of our lab is to define the phosphatases dysregulated in estrogen receptor (ER)-negative breast cancer. In the future, we will focus on determining those phosphatases critical for the induction and maintenance of ER-negative breast cancer by testing their ability to transform normal and pre-malignant cells and will investigate whether inhibitors of overexpressed phosphatases will be useful for the treatment of ER-negative breast cancer.

1. den Hollander P, Rawls K, Tsimelzon A, Shepherd J, Mazumdar A, Hill J, Fuqua SA, Chang JC, Osborne CK, Hilsenbeck SG, Mills GB, Brown PH. Phosphatase PTP4A3 Promotes Triple-Negative Breast Cancer Growth and Predicts Poor Patient Survival. Cancer Res 76(7):1942-53, 4/2016. e-Pub 2/2016. PMCID: PMC4873402.
2. Mazumdar A, Poage GM, Shepherd J, Tsimelzon A, Hartman ZC, Den Hollander P, Hill J, Zhang Y, Chang J, Hilsenbeck SG, Fuqua S, Kent Osborne C, Mills GB, Brown PH. Analysis of phosphatases in ER-negative breast cancers identifies DUSP4 as a critical regulator of growth and invasion. Breast Cancer Res Treat 158(3):441-54, 8/2016. e-Pub 7/2016. PMCID: PMC4963453.
3. Mazumdar A, Tahaney WM, Reddy Bollu L, Poage G, Hill J, Zhang Y, Mills GB, Brown PH. The phosphatase PPM1A inhibits triple negative breast cancer growth by blocking cell cycle progression. NPJ Breast Cancer 5:22, 2019. e-Pub 7/2019. PMCID: PMC6659706.
4. Bollu LR, Mazumdar A, Savage MI, Brown PH. Molecular Pathways: Targeting Protein Tyrosine Phosphatases in Cancer. Clin Cancer Res 23(9):2136-2142, 5/2017. e-Pub 1/2017. PMCID: PMC5413367.
5. Qian J, Ma Y, Tahaney WM, Moyer CL, Lanier A, Hill J, Coleman D, Koupaei N, Hilsenbeck SG, Savage MI, Page BDG, Mazumdar A, Brown PH. Correction: The novel phosphatase NUDT5 is a critical regulator of triple-negative breast cancer growth. Breast Cancer Res. 2024 Feb 5;26(1):23. doi: 10.1186/s13058-024-01778-w.
6. Tahaney WM, Qian J, Moyer CL, Nguyen N, Lanier A, Ma Y, Hill J, Powell RT, Davies PJA,  Mazumdar A, Brown. PH Inhibition of GPX4 Induces the Death of p53-Mutant Triple-Negative Breast Cancer. Breast Cancer Res Treat, 2026 Jan 6;215(2):49. doi: 10.1007/s10549-025-07865-6.

Our research interests focus on the early detection and prevention of estrogen receptor (ER)-negative breast cancer. We are studying the mechanisms of breast cancer growth to support development of novel molecular targets for cancer prevention and therapy. Additionally, we are investigating tumor cell-signaling events in order to determine the biological pathways involved in tumorigenesis. It is our goal to define these signaling strategies using in vitro and in vivo models in order to develop future therapeutic agents.

Breast cancer is the most common form of cancer and is the second most common cause of cancer-related death in women. Extensive studies have been conducted to identify agents for prevention of breast cancer. Results from recent clinical trials have demonstrated that anti-estrogens significantly prevent the development of ER-positive breast cancer by more than 50%.

Retinoids have been shown to prevent ER-negative mammary tumor development in animal models. Bexarotene has been shown to partially prevent breast cancer development in mice but has some toxic side effects. LG100268, a more selective rexinoid, has been developed and is expected to be a more effective chemopreventive agent for ER-negative breast cancer. Another RXR agonist IRX-4204 is more potent in preventing ER-negative and triple-negative breast cancer growth.

We have analyzed the effects of IRX 4204 in the MMTV-ErbB2 and BRCA1^co/co; MMTV-Cre^+/+; p53^+/- mouse model. The results of this study demonstrate that the rexinoid IRX 4204 effectively prevents ER-negative mammary tumorigenesis in these mice. These results identify IRX 4204 as a potentially critical therapeutic agent for the future prevention of breast cancers in women. We have also analyzed mTOR pathway inhibitor everolimus for the prevention of ER-negative and Triple-negative breast cancer.

1. Mazumdar A, Medina D, Kittrell FS, Zhang Y, Hill JL, Edwards DE, Bissonnette RP, Brown PH. The combination of tamoxifen and the rexinoid LG100268 prevents ER-positive and ER-negative mammary tumors in p53-null mammary gland mice. Cancer Prev Res (Phila) 5(10):1195-202, 10/2012. e-Pub 8/2012. PMID: 22926341.
2. Mazumdar A, Tahaney WM, Hill JL, Zhang Y, Ramachandran S, Kawedia J, Qian J, Contreras A, Savage MI, Vornik LA, Sei S, Mohammed A, Brown PH. Targeting the mTOR Pathway for the Prevention of ER-negative Breast Cancer. Cancer Prev Res (Phila) 15(12):791-802, 12/2022. PMCID: PMC9762336.
3. Moyer CL , Lanier  A, Qian J , Coleman D , Hill J,  Vuligonda  V,  Sanders ME, Mazumdar A , Brown PH. IRX4204 Induces Senescence and Cell Death in HER2-positive Breast Cancer and Synergizes with Anti-HER2 Therapy. Clin Cancer Res. 2024 Apr 5.doi: 10.1158/1078-0432.CCR-23-3839.
4. Moyer CL, Hill JL, Coleman D, Lanier A, Ma Y, Liu X, Kawedia J, Contreras A, Vuligonda V, Savage MI, Sanders ME, Mohammed A, Sei S, Brown PH, and Mazumdar A. Targeting the RXR Pathway for the Prevention of Triple Negative Breast Cancer. Cancer Prev Res (Phila), 2026 Mar 3;19(3):161-168. doi: 10.1158/1940-6207.CAPR-25-0081.

The identification of potential transcription factors critical for breast cancer development and growth is the focus of the third area of research within the Mazumdar Laboratory. These projects center on determining the transcription factors that play key roles in the development of ER-negative and/or ER-positive breast cancers.

The long term goal of our research is to develop novel and effective therapies to prevent and treat breast cancer. Over the last few years we have focused on the identification of promising molecular targets for this purpose. One of these potential targets is the activator protein 1 (AP-1) transcription factor, which we have demonstrated to be an important regulator of breast cell growth. Further investigation showed that loss of AP-1 activity by a specific AP-1 inhibitor (Tam67, a cJun dominant negative mutant) can suppress growth factor-induced breast cancer cell proliferation and arrest cell cycle progression at the G1 phase.

Estrogen receptors, members of the nuclear receptor super family, mediate most of the effects of estrogen in breast cancer. Estrogen stimulation of gene expression is complex and involves several different mechanisms. Our lab focuses on non-classical ER pathways that use TF crosstalk.

We have demonstrated that ER-AP-1 crosstalk is critical for breast cell proliferation, and through microarray analysis we have identified genes dependent upon AP-1 and estrogen signaling. Currently, we are investigating the mechanism by which ER and AP-1 regulate expression of one of these genes, c-myc.

C-myc is an oncogene that encodes a nuclear transcription factor. The cMyc protein regulates expression of a variety of target genes which control cell cycle progression, apoptosis, and cellular transformation. Deregulated expression of c-myc is observed in many cancers and is associated with poor prognosis. c-myc is frequently amplified and overexpressed in breast cancer and previous studies have shown that c-myc is a potential target for breast cancer prevention and treatment. We have identified a novel pathway in which ER and AP-1 transcription factor crosstalk at a distant enhancer element is involved in estrogen induction of c-myc expression. This alternative pathway of estrogen-regulated gene expression may be targeted in the future to improve prevention and treatment strategies of breast cancer.

The results from these studies provide the scientific rationale to develop drugs targeting inhibition of AP-1 or its downstream molecules for the prevention or treatment of breast cancer.

1. Liu Y, Ludes-Meyers J, Zhang Y, Munoz-Medellin D, Kim HT, Lu C, Ge G, Schiff R, Hilsenbeck SG, Osborne CK, Brown PH. Inhibition of AP-1 transcription factor causes blockade of multiple signal transduction pathways and inhibits breast cancer growth. Oncogene, 21: 7680-7689, 2002.
2. Liu Y, Lu C, Shen Q, Munoz-Medellin D, Kim H, Brown PH. AP-1 blockade in breast cancer cells causes cell cycle arrest by suppressing G1 cyclin expression and reducing cyclin-dependent kinase activity. Oncogene, 23: 8238-8246, 2004.
3. DeNardo DG, Kim HT, Hilsenbeck S, Cuba V, Tsimelzon A, Brown PH. Global gene expression analysis of estrogen receptor transcription factor cross talk in breast cancer: identification of estrogen-induced/activator protein-1-dependent genes. Mol Endocrinol, 19: 362-378, 2005.
4. Shen Q, Zhang Y, Uray IP, Hill JL, Kim HT, Lu C, Young MR, Gunther EJ, Hilsenbeck SG, Chodosh LA, Colburn NH, Brown PH. The AP-1 transcription factor regulates postnatal mammary gland development. Dev Biol, 295: 589-603, 2006.
5. Shen Q, Uray IP, Li Y, Zhang Y, Hill J, Xu XC, Young MR, Gunther EJ, Hilsenbeck SG, Colburn NH, Chodosh LA, Brown PH. Targeting the activator protein 1 transcription factor for the prevention of estrogen receptor-negative mammary tumors. Cancer Prev Res (Phila Pa). 2008 Jun;1(1):45-55.
6. Wang C, Mayer JA, Mazumdar A, Fertuck K, Kim H, Brown M, Brown PH. Estrogen induces c-myc gene expression via an upstream enhancer activated by estrogen receptor and activating protein-1 transcription factor. Mol Endocrinol, 25(9):1527-38, 2011.

Identification of transcription factors critical for the growth and treatment of breast cancer

RNA transcription profiling has enabled breast tumors to be defined in distinct subtypes (basal, luminal and HER2) which possess unique prognoses and treatment options. Key regulators, such as estrogen receptor alpha and HER2, have been identified for the luminal and HER2 subtypes, while master regulators for the basal tumors remain unknown. Recent studies have shown inherent distinctions between basal and luminal breast cancers at the transcriptional level. Since transcription factors (TFs) are able to directly regulate RNA transcription of multiple genes by binding cis-regulatory elements of DNA, resulting in the coordinated response of an entire gene set, TFs are promising candidates as master regulators of basal breast cancer. 

We hypothesize that specific TFs regulate the transcriptional profile related to basal breast cancer and the aggressive proliferation associated it. To test this hypothesis, we are using three independent screening approaches to identify specific TFs critical for the regulation of basal breast cancer.

First, we are identifying TF binding motifs which are over-represented among promoters of genes over-expressed in basal tumors. Second, we are querying breast cancer protein to identify TFs which bind labeled DNA probes in basal cell lines to a higher degree than in luminal cell lines. Finally, due to the open chromatin conformations characteristic of the regulatory regions bound by TFs, we are using formaldehyde-assisted isolation of regulatory elements (FAIRE) to identify regions of open chromatin in basal cells as well as the TFs which bind these regions. Candidate TFs identified through these screening techniques will be selected for further studies to define their roles in the regulation of basal gene expression and to ascertain which TFs are critical for the proliferation of basal breast cancer cells.

Identifying TFs which act as master regulators of the basal subtype will increase our understanding of the biology of basal-like tumors and, more importantly, will identify potential targets for future therapeutic strategies to treat this aggressive type of breast cancer.

1. Liu Y, Ludes-Meyers J, Zhang Y, Munoz-Medellin D, Kim HT, Lu C, Ge G, Schiff R, Hilsenbeck SG, Osborne CK, Brown PH. Inhibition of AP-1 transcription factor causes blockade of multiple signal transduction pathways and inhibits breast cancer growth. Oncogene, 21: 7680-7689, 2002.
2. Liu Y, Lu C, Shen Q, Munoz-Medellin D, Kim H, Brown PH. AP-1 blockade in breast cancer cells causes cell cycle arrest by suppressing G1 cyclin expression and reducing cyclin-dependent kinase activity. Oncogene, 23: 8238-8246, 2004.