Animal Model for Local Inflammation-Induced Breast Cancer

Project: Research project

Description

DESCRIPTION (provided by applicant): The theory that tumors originate from regions of chronic inflammation has recently received support from considerable evidence obtained from a series of animal and epidemiological studies. It is now apparent that there is an interplay between epithelial cells and inflammatory cells, particularly macrophages, which is critical for progression of breast cancer. The key player that links inflammation to cancer is the transcription factor NF-?B, which regulates the expression of genes involved in proliferation, anti-apoptosis, invasion and metastasis. Constitutive activation of NF-?B in breast cancer has been well established by us and others. We have identified a number of signaling pathways that cause constitutive NF-?B activation in cancer cells including the action of cancer cell-derived IL-1a and heregulin. Our studies have shown that mammary tumor cell line derived from transgenic mice expressing her2/neu oncogene have markedly increased NF-?B activation and proliferation upon exposure to tumor necrosis factor (TNF). The latter is a major factor secreted by tumor associated macrophages and in so doing links inflammation to cancer. Recent studies have shown that inhibition of NF-?B in cancer cells using genetic approaches leads to conversion from TNF-induced proliferation to TRAIL-induced cancer cell death. Thus, inhibitors of NF-?B are ideal for preventing progression of pre-neoplastic lesions to cancer. As genetic ablation of NF-?B in cancer cells is not clinically possible, we have developed a water-soluble compound LC-1 with potent anti-NF-?B activity. The NCI's RAID program has confirmed that this agent has a favorable pharmacokinetic profile for clinical development and as such the compound will be tested in a phase I clinical trial for leukemia in 2007. The goal of this proposal is to define the chemopreventive potential of this compound in two animal models of breast cancer. We will test the hypothesis that by inhibiting NF-?B activity in pre-neoplastic lesions, LC-1 converts inflammation-induced tumor growth to inflammation-induced tumor regression through TRAIL. We also hypothesize that LC-1 will be particularly effective on inflammatory breast cancers, a rare but deadly form of breast cancer that is critically dependent on NF-?B for growth and survival. Two aims will test these hypotheses. Aim 1 will be to determine the effect of LC-1 on mammary tumor incidence, multiplicity and its effect on the angiogenic switch in the inducible MMTV-neu model of breast cancer. The second aim will be to define the ability of LC-1 to reduce growth and angiogenesis in an inflammatory model of breast cancer. For aim I, we will use the recently developed inducible transgenic model of breast cancer where activated neu is induced by treating 6.5 week old females with doxycycline. The resultant mammary tumors in these mice show a specific pattern of progression with hyperplasia followed by the angiogenic switch and then development of invasive carcinoma followed by lung metastasis. This model will allow us to test the effect of LC-1 on each of these stages and to evaluate the effect of LC-1 on the levels of different immune modulatory cells in the tumor microenvironment during different stages of breast cancer. For the inflammatory breast cancer model, we will use SUM149 cells implanted in nude mice as these cells are extremely sensitive to LC-1 mediated cell death. This study has the potential for translation to clinic because LC-1 has a favorable pharmacokinetic profile with no major toxicity in the preclinical toxicology studies. We propose that we will not completely eliminate but control NF-?B activity (similar to the approach with beta-blockers for cardiovascular diseases) so that normal activity of immune system is not compromised with LC-1 treatment.
StatusFinished
Effective start/end date9/24/078/31/10

Funding

  • National Institutes of Health: $75,750.00
  • National Institutes of Health: $75,750.00

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Animal Models
Breast Neoplasms
Inflammation
Neoplasms
Inflammatory Breast Neoplasms
Cell Death
Growth
Pharmacokinetics
Tumor Necrosis Factor-alpha
Macrophages
Neuregulin-1
Neoplasm Metastasis
Clinical Trials, Phase I
Tumor Microenvironment
Doxycycline
Tumor Cell Line
Oncogenes
Nude Mice
Toxicology
Transgenic Mice

ASJC

  • Medicine(all)