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Role of Aromatase and COX-2 Inhibition in the Prevention of p53-Mediated Breast Cancer
Hormonal therapy is the most widely accepted long-term treatment for breast cancer. Tamoxifen and, recently, selective aromatase inhibitors have demonstrated their effectiveness against estrogen receptor (ER) positive tumors. These strategies are not offered to the 40% of women with ER-negative tumors. If we are to develop effective therapies against such breast cancers, we need to elucidate targets for intervention in key pathways using an appropriate preclinical model.
Accumulating evidence indicates that the p53 tumor suppressor pathway is pivotal in determining susceptibility to breast cancer. Mutations in TP53 occur in ~30% of breast cancers and are common features of ER-negative tumors. Non-mutational changes in p53 function may occur in up to 45% of breast cancers. Disruptions in the p53 pathway can alter proliferation, apoptosis, angiogenesis, genetic stability, survival of hypoxic stress, and response to therapy. Although loss of p53 function alone is significant, it is not sufficient for development of breast cancer. The p53 pathway integrates
a variety of genetic and hormonal cues that modulate susceptibility to breast cancer, including the production of estrogens by aromatase and prostaglandins by cyclooxygenase-2 (COX-2). The correlation of COX-2 with aromatase expression in human breast cancer tissue suggests an interaction that promotes tumor growth and enhances metastatic progression.
We hypothesize that breast cancer development, through the sequential inactivation of p53, is mediated by aromatase activity during early phase(s) of tumorigenesis (hormone-dependent). As tumor progression leads towards a complete loss of p53 function and ER response, tumorigenesis becomes mediated by COX-2 (hormone-independent). This adaptive progression from ER-positive to ER-negative may explain the aggressive nature of recurrent tumors, their poor prognosis with current treatment regimens, and the development of tamoxifen-resistance.
We propose using a p53-deficient mouse model to (1) elucidate the role of aromatase and COX-2 inhibitors against p-53 mediated breast cancer, and (2) identify and correlate tumor phenotypes with responses to aromatase and COX-2 inhibitors. Mice deficient in p53 (BALB/c-Trp53+/- and BALB/c-Trp53-/-) demonstrate a genetic predisposition to mammary tumor development that exhibits the major features of human breast cancer of ductal origin. These tumors develop from hyperplastic intermediates that express ER, and later evolve into poorly differentiated tumors that lose steroid receptor expression. The ability to retain hormone receptors in early neoplastic lesions provides an excellent model to determine the interaction of p53 with hormone status and aromatase activity. During the progression towards ER-negative tumors, subsequent loss of p53 function may lead to upregulation of COX-2 and increased invasive and metastatic potential.
We expect aromatase inhibitors will selectively suppress estrogen production in the breast or the tumor itself during the hormone-responsive phase of tumorigenesis. COX-2 inhibitors will act through anti-angiogenesis and pro-apoptosis, targeting their effect during the later stages. Results will provide information to predict tumor response, indicate prognosis, and identify potential targets for more effective therapy.
This proposed research will take three years. The results will provide invaluable preclinical data towards a strategy against ER-negative breast cancer.
The development of breast cancer is a series of pre-cancerous changes that must occur in the mammary gland before cancer is established. Even after cancer is established, changes can occur as the tumor adapts to treatments or other factors. The complexity of this developmental process results in different types of breast cancers that require different therapies. The effectiveness of hormonal therapy — tamoxifen and, recently, selective aromatase inhibitors — against estrogen receptor (ER) positive tumors creates limited options for the 40% of women with ER-negative tumors. If we are to develop effective therapies for women with such breast cancers, we need to understand the physiological pathways involved in tumor development and growth.
The p53 gene is the most common tumor suppressor gene mutated in all human cancers. Tumor suppressor genes interact with other genes through important physiological pathways to maintain normal cellular functions. Studies indicate that ER-negative cancers can develop when a woman’s p53 tumor suppressor pathway is ‘changed’. The p53 pathway is important because it integrates numerous genetic and hormonal cues that regulate the susceptibility of some women’s breast tissue to develop cancer. Studies suggest ‘changes’ can keep the p53 pathway from controlling two important enzymes: (1) aromatase, which produces estrogens in many tissues, and (2) cyclooxygenase-2 (COX-2), which produces prostaglandins. Overproductions of estrogens and prostaglandins have been linked to breast cancer. Furthermore, since high levels of aromatase and COX-2 enzyme activities often occur together in the breast, they may interact to promote breast cancer.
We believe that breast cancer development, due to ‘changes’ in the p53 tumor suppressor pathway,
is initially controlled by aromatase. Later, as the tumor progresses, breast cancer development is controlled by COX-2. This adaptive progression may explain how ER-negative breast cancers may develop from ER-positive breast tissue and pre-cancerous lesions.
To see if this is true, we propose to study mice that have a breast cancer development process similar to humans due to ‘changes’ in their p53 pathway. We will treat the mice with drugs that inhibit aromatase and COX-2 enzyme activities. The information we obtain will tell us: (1) if and how aromatase and COX-2 inhibiting drugs affect breast cancer development, and (2) what types of breast cancer respond to aromatase and COX-2 inhibiting drugs.
We expect aromatase inhibiting drugs will be most effective during the early phase(s) of breast cancer development, and COX-2 inhibiting drugs will be most effective during the later stages. Results will provide information to predict the response of tumors to therapy and identify new targets for intervention.
This proposed research will take three years. The results will provide invaluable preclinical data towards a strategy against ER-negative breast cancers.