Breast Cancer: Article¬†
Resource:¬†¬† Dr. Alan Prem Kumar Team Members:
Position:¬†¬†¬†¬† Senior Scientist Principal Investigator at National University of Singapore
Member:¬†¬†¬†¬†¬†Global Medical Research.org
Dr. Alan Prem Kumar, National University of Singapore
Professor Shazib Pervaiz, National University of Singapore
Associate Professor Marie Veronique Clement, National University of Singapore¬†¬†
Copyright 2008:¬† Dr. Alan Prem¬†Kumar.¬† All rights reserved.
In Singapore, about 1000 women are diagnosed with breast cancer each year and the number is increasing at an annual rate of 3%. Recently, a new approach to inhibit proliferation and increase cell death in breast cancer cell lines has given hope for the development of a new class of anticancer drugs. These new class of drugs are activators of peroxisome proliferator-activated receptor gamma (PPARg). In addition to its endogenous ligand (15dPGJ2), several synthetic thiazolidinedione ligands (rosiglitazone and pioglitazone) are already in clinical use for the treatment of type 2 diabetes. Breast cancer cells express high levels of PPARg, whereas normal breast cells express only a low level of this receptor. This suggested a possible role for ligand-activated PPARg as an anti-tumor agent in breast cancer. In addition to promoting terminal differentiation of malignant breast cells in vitro, PPARg activation has been shown to induce apoptosis and fibrosis in breast tumor cells injected in mice. Since then, independent studies have identified PPARg targets in breast cancer cell lines but none of these targets have been shown to be directly responsible for the anti-tumor activity of PPARg activation.
Studies have shown that significantly greater expression level of intracellular pH regulator, Na+/H+ exchanger 1 (NHE1) protein in carcinoma tissues, compared to that in normal tissues, is closely associated with the genesis and progression of tumors, suggesting NHE1 can be used as the target in the treatment of tumors, including breast cancer. We previously reported down regulation of NHE1 expression by direct silencing or pre-incubation with H2O2 led to tumor cells‚Äô growth arrest and sensitization to etoposide or staurosporine. Incidentally, a very recent study demonstrated antisense therapy targeting NHE1 gene in gastric cancer decreased invasive capacity, and loss of cloning efficiency, and tumorigenecity in nude mice. Therefore, down-regulation of NHE1 gene expression promises to be an avenue in the search for new strategies to induce breast cancer cells‚Äô growth arrest and increase sensitivity to anti-cancer treatment. The promoter elements that regulate expression of the human NHE1 gene are only partially understood. The involvement of transcription factors C/EBP, CREB, NFY, and other cis elements in the 5‚Äô flanking region of human NHE1 has been reported, however, these transcription factors have only been identified using in vitro experiments. We established that NHE1 is a novel target of PPARg, and that repression of NHE1 expression by PPARg a priori to sensitizing breast cancer cells to paclitaxel. To provide clinical relevance, histo-pathological analysis of breast cancer biopsies obtained from patients with type II diabetes receiving rosiglitazone showed a significant repression of NHE1 protein levels in the tumor itself compared to cases of diabetics patients treated without glitazones and non-diabetic patients, but not in the adjacent non-cancerous tissue for all cases. This could therefore have tremendous implications for the judicious use of PPARg ligands at low doses in combination chemotherapy regimens for an effective therapeutic response [Kumar et al., (2008) Ligand-induced Activation of Peroxisome Proliferator Activated Receptor Gamma Represses NHE-1 Expression in Human Breast Carcinoma Cells. (submitted)].
Estrogen is implicated in the development of breast cancer, based on data from both clinical and animal studies; risk factors associated with breast cancer reflect cumulative exposure of the breast epithelium to estrogen. Since about 70% of breast cancer patients have estrogen receptor alpha (ERa) positive tumors, ERa became a target for the treatment of ERa-positive breast cancer. SERMs which include the pure steroidal anti-estrogen ICI 182,780 (Fulvestrant) have proven to be effective in the treatment of hormone-responsive breast cancer. Resistance to these anti-estrogens, however, is a serious clinical problem today. About 40% of ERa-positive tumors fail to respond to anti-estrogen therapy, and most breast tumor patients that initially respond will eventually develop resistance. Hence, different interventions are needed for effective therapeutic management of breast cancer. In our attempt to elucidate the mechanism for PPARg mediated repression of NHE1, our preliminary results provide evidence that in ERa-positive breast cancer cells, presence of estrogen-activated ERa-PPARg complex relieves this repression by switching out PPARg‚Äôs repressive activity. More importantly, we show ligand-activated PPARg elicited anti-tumor activity with greater efficacy when this ERa-PPARg complex is disrupted via pre-treatment with anti-estrogen ICI 182,780 at a concentration where ICI 182,780 alone did not affect cells‚Äô viability. This breakthrough, together with our observation that PPARg-mediated a greater repression of NHE1 in estrogen-deprived serum, is of paramount importance for translation into clinic as a means to re-sensitize breast cancer patients who are resistant to anti-estrogen therapy alone. Our aim, as a corollary to understanding the mechanism(s) by which PPARg down-regulates NHE1 gene expression may therefore identify key regulators of PPARg‚Äôs anti-tumor activity and novel clinical targets for better improvement in breast cancer treatment, and that expression of NHE1 levels could provide useful prognostic information for breast cancer patients.
National University of Singapore:¬† Read more about Dr. Alan Prem Kumar's research.¬†
Kumar, A.P. (October, 2008). Breast Cancer.¬† Article submitted to Global Medical Research.org, Oct. 23, 2008.