The Role of N-CoR During Normal Mammary Gland Development

Institution: University of California, San Diego
Investigator(s): Sung Hee Baek, Ph.D. -
Award Cycle: 2000 (Cycle VI) Grant #: 6FB-0023 Award: $75,583
Award Type: Postdoctoral Fellowship
Research Priorities
Biology of the Breast Cell>Biology of the Normal Breast: the starting point

Initial Award Abstract (2000)
Our laboratory has a long-standing interest in the control of gene expression by steroid and other related nuclear receptors, which have proven critical for normal development and function, as well as in several types of human cancer.

Endocrine therapy, in particular the anti-estrogen tamoxifen, is now widely used for the treatment of breast cancer and the effect of all forms of this therapy teem to be mediated through receptors, especially the estrogen receptor. More that 80% of the tumor with functional estrogen receptor respond to tamoxifen therapy initially. However, although tamoxifen is the most prescribed drug for the treatment of human breast cancer, most or all patients eventually develop drug resistance in the course of therapy and, in most cases, this is not due simply to the loss of expression of estrogen receptor.

Recently, novel factors that play a key role in determining the action of nuclear receptors have been discovered. On the basis of their positive or negative effects on nuclear receptors, they are referred to as coactivators or corepressors. We believe that the anti-estrogens, such as tamoxifen, cause inability of recruitment of specific corepressor complex to the estrogen receptor, which in turn prevents the recruitment of factors called co-activators, that are normally required for the desired anti-estrogenic effects of tamoxifen in treatment of breast cancer. Resistance to these drugs could occur by one of several possible mechanisms including decreased levels of specific corepressor or inhibition of corepressor binding to estrogen receptor, or a block of the corepressor function. A support for this model, previous experiments have demonstrated that in the absence of the nuclear receptor corepressor N-CoR, tamoxifen is converted from an antagonist to an agonist. In addition, N-CoR expression levels seem to decrease in tumors that have developed resistance to anti-estrogens.

I will define the role of N-CoR in normal mammary gland development and determine if N-CoR plays a role in mammary tumorigenesis. I will generate mice in which N-CoR function is lost or gained. I predict that both deletion and addition will have profound effects on mammary epithelial cell proliferation and differentiation. These genetic approaches will allow us to directly analyze the role of N-CoR in growth and differentiation of mammary cells as well as to test its action as a breast disease susceptibility gene. Most importantly, once any mammary defects in these models have been characterized, the models could then be utilized to directly test if N-CoR is a critical component for tamoxifen to act as an inhibitor rather than an activator of estrogen receptor.

Final Report (2002)
The tumors of many women with breast cancer are initially estrogen receptor (ER) positive and these tumors depend on estrogen for their growth. The contribution of nuclear receptors to the proliferation of breast tumors is well-studied, and anti-estrogen therapy using tamoxifen is widely used in breast cancer treatment. Basic studies of the mechanisms of ER and tamoxifen actions have permitted new insights and approaches to breast cancer diagnosis and therapy.

In the presence of tamoxifen, ER then binds to N-CoR. Tamoxifen causes ER to associate with the N-CoR corepressor complex, which is required for its anti-estrogen effect. The ability of N-CoR to function as a repressor of ER-mediated transactivation suggests that N-CoR may play an important role not only during normal mammary gland development, but also in the process of breast tumorigenesis and the acquired resistance to tamoxifen treatment.

In order to address the biological role of N-CoR during mammary gland development in relationship to ER localization, immunohistochemistry was performed for N-CoR and ER. This revealed a progressive decrease of N-CoR and the translocation of N-CoR to the cytoplasm in response to specific signals. In the absence of N-CoR, tamoxifen acts to stimulate ER transcription. Based on the observations, the biological role of N-CoR and relationship of N-CoR to the process of breast cancer as well as mammary gland biology was investigated. A novel corepressor complex, dismissed by specific cytokines, permitted activation of target gene. These studies will impact the diagnosis and treatment of human breast cancer.

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Index Medicus: Cell
Authors: Kioussi, Briata, Baek, Rose, Natasha, Hamblet, Herman, Ohgi, Lin, Gleiberman, Wang, et al.
Yr: 2002 Vol: 111 Nbr: Abs: Pg:673-685

Exchange of N-CoR Corepressor and Tip60 Coactivator Complexes Links Gene Expression by NF-xB and -Amyloid Precursor Protein
Index Medicus: Cell
Authors: Sung Hee Baek, Kenneth A. Ohgi, David W. Rose, Edward H. Koo, Christopher K. Glass, and Mi
Yr: 2002 Vol: 110 Nbr: Abs: Pg:55-67