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Small animal ultrasound to examine the role of AIB1 and its isoform in estrogen receptor alpha-initiated preneoplasia and DCIS
Background: Amplified in Breast Cancer 1 (AIB1), a p160 nuclear receptor coactivator family member, is involved in steroid receptor-mediated transcription. The AIB1 gene is amplified in 5-10% of breast cancers, suggesting that AIB1 plays an important role in breast cancer progression. AIB1 directly interacts with estrogen receptor alpha (ERa) and enhances ER-dependent transcription in breast cancer cells.
Objective/Hypothesis: AIB1’s in vivo role in ERa-initiated preneoplasia and ductal carcinoma in situ (DCIS) will be examined in mouse models. We hypothesize that AIB1 overexpression in the ERa DCIS model will stimulate proliferation and activate growth signaling pathways, leading to mammary gland (MG) density changes which can be followed during cancer progression using novel imaging techniques. Conversely, loss of AIB1 action will prevent carcinogenesis.
Specific Aims: 1.) Follow changes in MGs with ERa dysregulation and AIB1 gain or loss using ultrasonography (US) and reflectance confocal microscopy (RCM), 2.) Compare AIB1 gain/loss effects on MG development, morphology, and ERa signaling pathways, and 3.) Examine interaction of ERa and AIB1 gain/loss on IGF signaling in MG development, growth and differentiation.
Study Design: Conditional transgenic mice with dysregulated ERa have been bred to mice with AIB1 overexpression or loss. MGs will be examined from mice at different stages of cancer development to determine perturbations in signaling pathways, growth, proliferation, apoptosis, and differentiation during progression of preneoplasia. US imaging will prospectively monitor MG density changes during carcinogenesis. RCM will yield unprocessed real-time imaging of MG ductal epithelial cell morphology. Density and epithelial changes will be correlated with MG histology and morphology. Collaboration between ERa, AIB1, and IGF signaling pathways during MG development will be examined using MG whole organ culture.
Outcomes/Benefits: We will study cancer progression in ERa-initiated mammary carcinogenesis. Dysregulated ERa expression in mammary epithelial cells is a significant risk factor for development of preneoplasia, however further mechanistic study of ERa signaling through its coactivator, AIB1, in initiation and progression of breast carcinogenesis is necessary to understand roles these molecules play in breast cancer pathogenesis. ERa may collaborate with AIB1 to cause progression of DCIS which can be non-invasively followed by breast imaging. This will have implications for breast cancer detection, diagnosis, and surveillance.
Breast cancer is the most common female cancer and the second leading cause of cancer deaths in women in the U.S. Early detection is essential to save lives and increase treatment options. Mammography has improved early stage breast cancer detection before symptoms become evident and cancer invades. Ductal Carcinoma in Situ (DCIS) is an early stage in breast cancer (preneoplasia) which progresses to invasive cancer in 25-50% of cases if not detected in time. Understanding what causes DCIS, how DCIS leads to cancer, and which molecules are involved in the process will lead to targeted, more effective, less toxic chemoprevention and chemotherapy for women with DCIS.
The female hormone estrogen works in breast cells through estrogen receptor alpha (ERa), to stimulate normal cell growth. Having more ERa than normal in breast cells may indicate uncontrolled cell growth, a significant cancer risk factor. ERa interacts with Amplified in Breast Cancer 1 (AIB1), a coactivator, which is increased in human breast cancers and also causes uncontrolled cell growth and proliferation. We hypothesize that overexpression of both AIB1 and ERa will cause DCIS to progress to cancer.
The project goals are to use a mouse model that resembles human breast cancer to study how overexpression of both AIB1 and ERa leads to uncontrolled cell growth, DCIS, and breast cancer. Mouse models are important for investigating how preneoplasia develops into cancer in response to specific genetic changes, since these lesions cannot be addressed easily in tissue culture cells. Changes in mammary gland (MG) of transgenic mice will be monitored from preneoplasia to DCIS development in real-time using ultrasound imaging technology and a special microscope that visualizes mammary cell morphology in intact, live mice. These imaging techniques will help identify areas of dense MG tissue, a predictor of increased breast cancer risk, and will allow us to follow cancer progression in these mice.
This proposal could lead to improvements in health by providing essential information on ER and AIB1. These data will help advance breast cancer detection, diagnosis, and surveillance to identify cancers at earlier, more treatable stages, increasing the chance of cure. The overall goal is to identify molecular targets to develop novel therapeutic approaches for early detection and more effective treatments for patients at high risk for invasive breast cancer. Lastly, we anticipate that these mouse models could be used to test novel therapies for DCIS before clinical use in humans.