Introduction: Ductal Carcinoma In Situ (DCIS) has become the most diagnosed breast tumor type in North America. Amplified In Breast Cancer 1 (AIB1) is amplified in 5 to 10 % of primary breast tumors. We have recently demonstrated that AIB1 causes development of DCIS lesions in the mammary gland of 30% of the AIB1 transgenic mice (1). Our laboratory has also shown that deletion of one allele of AIB1 prevents HER2-induced mammary tumor development in mice (2), suggesting a pivotal role of AIB1 during earlier stage of breast cancer. We hypothesize that AIB1-mediated pathways promote the transformation of the mammary epithelial cells and the alterations of the functional integrity of the mammary gland. By contrast, decrease in AIB1 functionality may result in prevented DCIS initiation and arrested breast tumor progression.
Results: We showed by immunohistochemistry that AIB1 is expressed at low levels in normal human breast. By contrast, we observed a strong cytoplasmic and/or moderate nuclear AIB1 protein expression in DCIS lesions in breast cancer patients tissues. We investigated the impact of decreasing AIB1 expression on the early transformed MCFDCIS cell line. MCFDCIS cells generate multiacinar disorganized structures with filling of the lumen, loss of polarization and escape from the proliferative suppression. Reduction of AIB1 in human MCFDCIS cells restored a more normal mammary acinar structure with basement membrane in 3D growth in MatrigelTM. Then, we studied the effect of regulating AIB1 on the histopathology development of the DCIS lesions in a xenograft mouse model by subcutaneously injecting MCFDCIS cells deficient or not in AIB1 into nude mice. The MCFDCIS xenografted tumors obtained reproduced the human breast cancer progression and displayed multiple comedo DCIS-like lesions. Decreased levels of AIB1 in MCFDCIS cells, either prior to DCIS development or in existing MCFDCIS lesions in vivo, inhibited tumor growth and led to smaller, and necrotic lesions.
Conclusions: Altogether, these data suggest that increased expression of AIB1 facilitates the genesis and progression of DCIS to invasive disease. Thus, targeting AIB1 may represent a new therapeutic paradigm to prevent disease progression especially for women with AIB1-positive primary tumor. The results of this project will also serve as basis of human clinical studies that may define new predictive and prognostic biomarkers that recognize high-risk patients, and prevent over- or undertreatment of breast cancer patients.
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Citation Format: Virginie Ory, Elena Tassi, Luciane Cavalli, Francisco Saenz, Tabari Baker, Susette Mueller, Priscilla Furth, Anton Wellstein, Anna Riegel. The nuclear coactivator amplified in breast cancer 1 promotes the initiation and the development of ductal carcinoma in situ. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1404. doi:10.1158/1538-7445.AM2013-1404