The ability of the mammary gland to undergo tumorigenesis is influenced by its normal development, including reproductive endocrine events. It is increasingly accepted that mammary gland development and tumorigenesis are fundamentally linked, and perturbations in the expression or function of steroidal coactivators and corepressors or its associated targets can contribute to the etiology of steroidal cancers. We propose here to investigate the influence of metastatic tumor antigen 1 (MTA1) on the reproductive biology of the mammary gland using in vitro, transgenic mouse models, and potential roles of MTA1 and a naturally occurring variant MTA1s in the early stages of breast cancer development. In addition, cyclin D1, an established oncogene and regulator of cell cycle progression, is a common downstream target of diverse upstream signals with a role in mammary gland development and tumorigenesis. Here we propose to investigate the influence of MTA1 and its downstream target cyclin D1 on the reproductive endocrinology and development of the mammary gland and early stages of breast tumor formation using novel model systems and human tumor specimens. The rationale for this proposal is based on Preliminary data by the PI showing that MTA1 promotes anchorage-independent growth, and upregulate cyclin D1 expression. A naturally occurring spliced variant known as """"""""MTA1s"""""""" sequesters ER in the cytoplasm and stimulates anchorage-independent growth and tumorigenicity of breast cancer cells. MMTV-MTA1 transgene expression in a mouse model results in abnormal lateral branching and alveolar development, increased cyclin D1, and hyperplastic nodules in mammary glands from virgin females. We interpret these findings as suggesting that MTA1 may have significant roles in normal mammary development by controlling expression and consequently, functions of its putative target genes such as cyclin DI. Our working hypotheses are that MTA1 play regulatory functions during normal mammary gland development and that deregulation of the MTA1 may induce alterations including, upregulation of cyclin D1 pathway, involved in early stages of breast tumor development.
The specific aims of this proposal are to study: (1) The influence of MTA1 transgene expression on the biology, development and tumorigenesis of mammary gland; (2) The mechanistic role of cyclin D1 in the action of MTA1 and whether these two proteins cooperate during mouse mammary gland tumorigenesis; (3) The expression characteristics of MTA1 and MTAls and cyclin D1 during multi-step pathogenesis of breast carcinoma and to evaluate its prognostic value in-patients with invasive breast cancer. An innovative aspect of this proposal is the use of novel models to gain insights about the roles of MTA1 and MTA1s as critical pathways in the reproductive biology of mammary gland in the pathophysiologically relevant experimental setting.
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