ISSN: 2161-0479
Journal of Autacoids and Hormones
Like us on:
Make the best use of Scientific Research and information from our 700+ peer reviewed, Open Access Journals that operates with the help of 50,000+ Editorial Board Members and esteemed reviewers and 1000+ Scientific associations in Medical, Clinical, Pharmaceutical, Engineering, Technology and Management Fields.
Meet Inspiring Speakers and Experts at our 3000+ Global Conferenceseries Events with over 600+ Conferences, 1200+ Symposiums and 1200+ Workshops on Medical, Pharma, Engineering, Science, Technology and Business
Editorial Open Access
Inflammatory Breast Cancer is Associated with Hyperactivated Mitogen Activated Kinase
| Robert L. Copeland Jr.1,3* and Yasmine M. Kanaan2,3 | ||
| 1Department of Pharmacology, Howard University, Washington, DC, USA | ||
| 2Department of Microbiology, Howard University, Washington, DC, USA | ||
| 3College of Medicine and Cancer Center, Howard University, Washington, DC, USA | ||
| Corresponding Author : | Robert L. Copeland Jr. Department of Pharmacology Howard University, Washington, DC, USA E-mail: rlcopeland@Howard.edu |
|
| Received May 11, 2012; Accepted May 14, 2012; Published May 16, 2012 | ||
| Citation: Copeland RL Jr, Kanaan YM (2012) Inflammatory Breast Cancer is Associated with Hyperactivated Mitogen Activated Kinase. J Autacoids 1:e114. doi: 10.4172/2161-0479.1000e114 | ||
| Copyright: © 2012 Copeland RL Jr, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. | ||
Related article at Pubmed Scholar Google |
||
Visit for more related articles at Journal of Autacoids and Hormones
| Inflammatory Breast Cancer (IBC) is a distinct clinical subtype of locally advanced breast cancer, with a particularly aggressive behavior and poor prognosis. Clinically, IBC typically presents with rapidly progressive breast warmth, erythema and edema [1]. It is now well established that adjuvant systemic therapy improves survival in patients with early-stage breast cancer [2]. Breast cancer is highly curable if diagnosed at early stage. Recent progress in diagnosis and therapy has increased the survival of women in estrogen-dependent breast cancer. However, despite advances in multidisciplinary treatment, the prognosis of IBC is less favorable than of non-IBC, with a 3-year survival of about 40% [3,4]. Activation of NF-κB in inflammatory breast cancer is associated with loss of Estrogen Receptor (ER) expression, indicating a potential crosstalk between NF-κB and ER. It has been shown that NF-κB activation is not exclusively limited to IBC but more general to ERα- breast tumors. | |
| Determination of estrogen receptor (ER) status of invasive breast carcinoma is useful as a prognostic and predictive factor and has become standard practice in the management of this type of cancer. Breast cancer presents as either estrogen positive (ERα+) or receptor negative (ERα-). ERα + tumors have a better prognosis in terms of increased disease-free survival and respond to hormonal therapies such as tamoxifen [5-7]. Whereas, ERα- breast cancers have a worse prognosis and are associated with a more aggressive phenotype, are resistant to anti-estrogens, and frequently present with elevated growth factor receptor expression and/or signaling with resultant p42/44/ Mitogen Activated Kinase (MAPK) signaling [8-10]. Signal transduction by way of Mitogen Activated Protein (MAP) kinases is an integral part of many cellular responses. These responses include proliferation, differentiation, and cell death. Upwards of a dozen highly genetically conserved MAP kinase families have been identified since their initial discovery in yeast. In mammalian cells, several distinct MAPKs have been identified. These include Extracellular signal Regulated Kinase (ERK) 1/2 cascades, c-Jun N-Terminal Kinase (JNK) or Stress Activated Protein Kinase 1 (SAPK1), and p38 MAPK also known as SAPK2. ERK 1/2 are often activated by mitogens and regulate cell growth and differentiation, while the JNK and p38 MAPK are poorly activated by mitogens and typically function in stress responses such as inflammation and apoptosis [11,12]. | |
| Determination of estrogen receptor (ER) status of invasive breast carcinoma is useful as a prognostic and predictive factor and has become standard practice in the management of this type of cancer. Breast cancer presents as either estrogen positive (ERα+) or receptor negative (ERα-). ERα + tumors have a better prognosis in terms of increased disease-free survival and respond to hormonal therapies such as tamoxifen [5-7]. Whereas, ERα- breast cancers have a worse prognosis and are associated with a more aggressive phenotype, are resistant to anti-estrogens, and frequently present with elevated growth factor receptor expression and/or signaling with resultant p42/44/ Mitogen Activated Kinase (MAPK) signaling [8-10]. Signal transduction by way of Mitogen Activated Protein (MAP) kinases is an integral part of many cellular responses. These responses include proliferation, differentiation, and cell death. Upwards of a dozen highly genetically conserved MAP kinase families have been identified since their initial discovery in yeast. In mammalian cells, several distinct MAPKs have been identified. These include Extracellular signal Regulated Kinase (ERK) 1/2 cascades, c-Jun N-Terminal Kinase (JNK) or Stress Activated Protein Kinase 1 (SAPK1), and p38 MAPK also known as SAPK2. ERK 1/2 are often activated by mitogens and regulate cell growth and differentiation, while the JNK and p38 MAPK are poorly activated by mitogens and typically function in stress responses such as inflammation and apoptosis [11,12]. | |
| Regardless of the different potential mechanisms for downregulating/ restoring ERα expression, the reexpressed ERα must not only be functional on reexpression (i.e., induce the regulation of estrogen-responsive genes) but must also be able to regulate growth in response to estrogen/antiestrogens to be clinically relevant. Overall, these data point towards that NF-κB and MAPK might be therapeutic targets for IBC specifically and more general for ERα- breast tumors as well as for breast tumors with acquired resistance against hormonal therapy. | |
| Current treatment methods of breast cancer, depending on the stage of cancer upon diagnosis, include surgery, radiation therapy, biological therapy, hormone therapy (e.g. tamoxifen, aromatase inhibitor) and chemotherapy (e.g. anthracyclines, taxanes). The most widely used therapy for breast cancer is the use of antiestrogen such as tamoxifen. However, the present breast cancer therapies achieve meaningful clinical results in only 30-40% of patients because drug resistance is linked to the presence of estrogen-independent pathways for breast cancer cell growth [15]. Therefore, more potent anti-breast cancer agents that combine the desired, tissue-selective effects with novel structures or new mechanism(s) of action must be developed. A number of 1,4-naphthoquinone derivatives have been found to possess powerful pharmacological effects associated with marked antimicrobial and antitumor activities [16]. | |
| Naphthoquinones, widely distributed in nature, play important physiological roles in animals and plants. Quinone derivatives may be toxic to cells by a number of mechanisms including redox cycling, arylation, intercalation, induction of DNA strands breaks, generation of free radicals and alkylation via quinonemethide formation [17,18]. As a consequence, the molecular framework of a great number of pharmaceuticals and biologically important compounds contain a quinone moiety. Representative examples of this class of compounds are the well-known anticancer drugs of the anthracycline series, doxorubicin and mitoxanthrone, the action of which is believed to occur via topoisomerase II inhibition [19]. In addition, a number of naphthoquinone analogues such as plumbagin, shikonin and naphthazarin as well as 3-lapachone have also been found to inhibit topoisomerase. The MAPK signaling pathway may be initiated by activation of either the EGFR or erbB-2 growth factor receptors from which the signal is channeled via Ras, Raf, and MEK, ultimately resulting in activating phosphorylation of MAPK and gene transcription [20]. Copeland et al. [21] reported the synthesis and effects of 2,3-Dichloro- 5,8-Dimethoxy-1,4-Naphthoquinone (DCDMNQ) derivatives which showed significant cytotoxicity against prostate and breast cancer cell lines. Mechanistically, it was shown that these compounds cause inhibitory effects on MAPK phosphorylation, thereby decreasing activity. Moreover, corresponding data suggest the ability of these compounds to have significant selective cytotoxicity against breast cancer cells as compared to normal bone marrow cells [22]. | |
| The abrogation of the MAPK pathway by direct inhibition of hyperactivated MAPK or possible upstream inhibition of overexpressed EGFR, c-erbB-2, or epigenetic alterations of the ERα gene promoter region, will result in re-expression of ERα. Thus, DCDMNQ may restore estrogen-dependence and anti-estrogen sensitivity in a subset of ERα- breast cancers, while contrasting the data with corresponding studies in ERα+ breast cancer cell lines. The roles of MAPK hyperphosphorylation, chromatin remodeling will provide detailed insight into the mechanisms employed by the compounds for ERα re-expression. Alternate estrogen receptor signaling pathways would further elucidate the role of these naphthoquinone analogs in breast cancer. The down-regulation of the ERα expression by hyperactive MAPK is a direct mechanism which is potentially reversible DCDMNQ analogs. However, alternative chromatin remodeling through ER regulators and histone deactylases, can potentially restore ERα expression, would increase anti-estrogen responsiveness in ERα- breast cancer cells. Therefore, ERα- breast cancer patients could benefit from combinatorial treatment with DCDMNQ analogs and conventional chemo/hormonal therapy. | |
| References | |
|
|
Relevant Topics
Recommended Journals
Article Tools
Article Usage
- Total views: 13863
- [From(publication date):
November-2012 - Aug 16, 2024] - Breakdown by view type
- HTML page views : 9450
- PDF downloads : 4413
