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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA098823-01A1
Application #
6682968
Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
Macleod, Carol L
Project Start
2003-07-01
Project End
2007-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
1
Fiscal Year
2003
Total Cost
$268,780
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Microbiology/Immun/Virology
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Kumar, Rakesh; Wang, Rui-An (2016) Structure, expression and functions of MTA genes. Gene 582:112-21
Li, Da-Qiang; Kumar, Rakesh (2015) Unravelling the Complexity and Functions of MTA Coregulators in Human Cancer. Adv Cancer Res 127:1-47
Ohshiro, Kazufumi; Kumar, Rakesh (2015) MTA1 regulation of ER? pathway in salivary gland carcinoma cells. Biochem Biophys Res Commun 464:1016-1021
Li, Da-Qiang; Yang, Yinlong; Kumar, Rakesh (2014) MTA family of proteins in DNA damage response: mechanistic insights and potential applications. Cancer Metastasis Rev 33:993-1000
Kumar, Rakesh (2014) Functions and clinical relevance of MTA proteins in human cancer. Preface. Cancer Metastasis Rev 33:835
Sen, Nirmalya; Gui, Bin; Kumar, Rakesh (2014) Physiological functions of MTA family of proteins. Cancer Metastasis Rev 33:869-77
Sen, Nirmalya; Gui, Bin; Kumar, Rakesh (2014) Role of MTA1 in cancer progression and metastasis. Cancer Metastasis Rev 33:879-89
Li, Da-Qiang; Pakala, Suresh B; Reddy, Sirigiri Divijendra Natha et al. (2013) Metastasis-associated protein 1 is an integral component of the circadian molecular machinery. Nat Commun 4:2545
Nair, Sujit S; Li, Da-Qiang; Kumar, Rakesh (2013) A core chromatin remodeling factor instructs global chromatin signaling through multivalent reading of nucleosome codes. Mol Cell 49:704-18
Pakala, Suresh B; Rayala, Suresh K; Wang, Rui-An et al. (2013) MTA1 promotes STAT3 transcription and pulmonary metastasis in breast cancer. Cancer Res 73:3761-70

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