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    Research Grants Awarded

    Disrupted Estrogen Signaling Pathways Collaborate With Loss Of P53 In The Development Of Preneoplasia In Breast Cancer

    Grant Mechanism:
    Postdoctoral Fellowships

    Scientific Abstract:
    Deregulated expression of estrogen receptor alpha (ERa) in normal breast epithelium has been found in conjunction with breast cancer, leading to the concept that loss of the normal regulatory mechanisms that control expression levels of ERa in normal breast epithelium may increase the risk for the development of breast cancer. Mutations in the tumor suppressor p53 are observed in one-third of human breast cancers and are reported in about 25% of all ductal carcinoma in situ (DCIS). It is suggested that p53 is likely to be involved in the beginning of breast carcinogenesis and impaired differentiation of DCIS, but not in the progression to invasive carcinoma. These findings suggest that p53 mutations are particularly involved in the development of breast cancer, making it a key factor when treating pre-invasive breast lesions. Estrogenic action results in the over expression of cellular factors responsible for the suppression of apoptosis and promoter of cellular proliferation during tumorigenesis, including cyclins D1 and E which we hypothesize could be altered by p53 heterozygosity. The current treatment for hormone-dependent breast cancer patients consists of the inhibition of estrogen action with antiestrogens, and the inhibition of estrogen synthesis with aromatase inhibitors. One of the mechanisms associated with resistance to both tamoxifen and the aromatase inhibitor letrozole is reduced levels of ERa expression and, as shown in some studies, downstream genes such as progesterone receptor, and phosphorylated ERK1/2 with an increase in genes in the MAPK pathway. To our knowledge there are no published studies on whether or not p53 mutation alters the response to aromatase therapy. The rationale for this study is that there is evidence that p53 mutations result in a worse overall survival to anti-hormonal therapy, however there are some conflicting results and a mechanism has not been clearly established. Moreover, it is not known if a mixed ERa antagonist/agonist such as tamoxifen or an aromatase inhibitor such as letrozole would be a better approach for anti-hormonal therapy when p53 mutation is present. The central hypothesis of this proposal is that loss of p53 collaborates with deregulation of ERa and/or increased local aromatase leading to abnormal hormonally induced growth of mammary epithelial cells, preneoplasia, DCIS and invasive cancer and may contribute to an impaired response to anti-hormonal therapies. We suggest that there may be a difference in efficacy when comparing tamoxifen versus letrozole. In this study we will employ mouse models to investigate how loss of p53 can alter development and progression of DCIS in both the absence and presence of mammary targeted aromatase over expression. The specific aims of the proposed research will: a) test how loss of p53 collaborates with deregulated ERa expression in the absence and presence of aromatase over expression to promote development of preneoplasia and DCIS in the mammary gland and b) determine if loss of p53 promotes development of resistance to tamoxifen and/or aromatase therapy in mice with deregulated ERa expression in the absence and presence of aromatase over-expression. Experimental (MMTV-rtTA/tet-op-ERa/p53+/-: Conditional Estrogen Receptor in Mammary tissue or CERM/p53+/-) and CERM/tet-op-Arom/p53+/- (CERM/Arom/p53+/-) and control (CERM/p53+/- and CERM/Arom/p53+/+) will be used to test how p53 heterozygosity influences disease progression and response to anti-hormonal therapy. For progression studies mammary glands will be collected at 12 months of age for morphological, histological, and gene expression studies both in intact nulliparous mice and in ovariectomized mice that have been treated with either placebo, estrogen or the combination of estrogen and progesterone to dissect the molecular events attributable to specific hormonal stimulation as compared to normal ovarian function in the absence and presence of local aromatase over expression. The expected outcome is that p53 heterozygosity will promote progression of mammary preneoplasia and cancer, that the effect will be more pronounced in the presence of aromatase over expression and that the combination of exogenous estrogen and progesterone with aromatase over expression will result in the most disease. To determine if p53 heterozygosity alters the response to tamoxifen or the anti-aromatase inhibitor letrozole in the absence or presence of aromatase over expression, nulliparous mice will be pelleted with tamoxifen or letrozole at 10 months of age, and mammary glands collected at 12 months of age and processed as above. As a control another group of mice will be withdrawn from doxycycline to turn off the conditional transgenes to down-regulate ERa and local aromatase over expression in the mammary gland. The expected outcome is that p53 heterozygosity will increase the development of resistance to anti-hormonal therapy but we suggest it is possible that letrozole may be more effective than tamoxifen. If a difference were to be shown it could stimulate interest in developing a clinical trial to determine if there was a specific benefit to using a specific class of anti-hormonal therapy in women whose breast cancers carry a p53 mutation.

    Lay Abstract:
    Breast cancer is the second leading cause of cancer death in women. Breast cancer develops as genetic changes accumulate giving rise to precursor lesions, which may progress to ductal carcinoma in situ (DCIS) and eventually invasive breast cancer. This process is often accompanied by mutations in the tumor suppressor gene p53. A tumor suppressor gene is a gene that reduces the probability that a cell will turn into a tumor cell. A mutation of such a gene will increase the probability of the formation of a tumor. The incidence of DCIS of the breast continues to rise and will account for an estimated 26% of new breast cancer cases in 2007. Mutations in the tumor suppressor p53 are observed in one-third of human breast cancers and are reported in about a quarter of all DCIS. A receptor (e.g. estrogen receptor alpha or ERa) is a protein that binds to a specific molecule or ligand (e.g. estrogen) and initiates the cellular response to the ligand. Estrogens are synthesized by an enzyme called aromatase. About 70% of human breast cancers are ERa positive and depend on estrogen for tumor growth. The selection of therapy for this type of breast cancers is traditionally based on average results from randomized clinical trials. The current treatment consists of the inhibition of estrogen action with antiestrogens (e.g. tamoxifen), and the inhibition of estrogen synthesis with aromatase inhibitors (e.g. letrozole). Unfortunately, a significant number of patients develop recurrent cancers and the recurrent tumors are resistant to tamoxifen and/or aromatase inhibitors treatment. Therefore, it is highly valuable to have mouse models developing ERa positive mammary lesions to study ERa signaling pathways to use to develop optimal therapeutic and chemopreventive strategies to treat these lesions. Studies have associated p53 mutations with a worse clinical outcome to anti-hormone therapy with tamoxifen, suggesting that p53 might induce resistance in certain modalities of breast cancer treatment. The hypothesis of this proposal is that loss of p53 collaborates with deregulation of ERa and/or increased local aromatase leading to abnormal hormonally induced growth of mammary epithelial cells, preneoplasia, DCIS and invasive cancer and an impaired response to anti-hormonal therapies. This proposal will use unique conditional mouse models of deregulated ER? as well as aromatase over expressing in the mammary gland, in combination with a loss of p53 mouse model. The proposed research will test how loss of p53 collaborates with deregulated ERa expression in the absence and/or presence of estrogen over production in the mammary gland, as well as determine if loss of p53 promotes the development of resistance to tamoxifen and aromatase inhibitors in mice with deregulated ERa expression in the presence and/or absence of estrogen over production. The experimental group will consist of mice with deregulated ERa with/without over production of estrogens in the mammary gland with loss of p53 and the control group will consist of mice with deregulated ER? with/without over production of estrogens in the mammary gland with fully functional p53. First, we will ask if loss of p53 promotes progression of peneoplasia towards DCIS and invasive cancer in the absence or presence of aromatase over expression. We will test if the type of hormonal stimulation influences this progression by examining mice with their ovaries intact, mice that have been ovariectomized and mice that have been ovariectomized and treated with either estrogen alone or the combination of estrogen and progesterone. The expected outcome is that p53 heterozygosity will promote progression of mammary preneoplasia and cancer, that the effect will be more pronounced in the presence of aromatase over expression and that the combination of exogenous estrogen and progesterone with aromatase over expression will result in the most disease. Then we will ask if loss of p53 alters the response to two common anti-hormonal therapies: tamoxifen and the aromatase inhibitor letrozole in the absence and presence of aromatase over expression. The expected outcome is that loss of p53 will decrease responsiveness to anti-hormone therapy but we suggest that there may be a difference in efficacy between tamoxifen and letrozole. If a difference were to be shown it could stimulate interest in developing a clinical trial to determine if there was a specific benefit to using a specific class of anti-hormonal therapy in women whose breast cancers carry a p53 mutation. Understanding the genetic and molecular events leading to the development of breast disease and how specific genetic changes alter the response to therapy could lead to the incorporation of more individualized therapies, reducing the percentage of mortality in breast cancer, and increasing the quality of life in our patients.