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Targeting Transcription Factors for the Prevention and Treatment of Breast Cancer


Mechanisms of estrogen-regulated stimulation of gene expression. In this study, our lab is focused on the central “Non-Classical” Pathway by which ER and AP-1 transcription factor crosstalk regulates estrogen-mediated induction of c-myc expression.

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.

References:

  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.

Lab members working on this research:

Chunyu Wang, Ph.D., and Jonathan Shepherd.


© 2014 The University of Texas MD Anderson Cancer Center