The Role of Estrogen-Related Receptors in Breast Cancer

Institution: Scripps Research Institute
Investigator(s): Anastasia Kralli, Ph.D. -
Award Cycle: 2006 (Cycle 12) Grant #: 12IB-0010 Award: $278,106
Award Type: IDEA
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease



Initial Award Abstract (2006)
Alterations in the metabolism of tumor cells are though to be important for cancer progression, by promoting aggressive growth and/or the ability of tumors to invade the surrounding tissue. The small family of Estrogen-Related Receptors (ERR) consists of three proteins that control the expression of many genes important for the cellular metabolic state. The three Estrogen-Related receptors, ERRα, ERRβ, and ERRγ, share significant sequence homology with ERs, but are not activated by natural estrogens. The ability of ERRs to recognize similar DNA sequences as ERs and to regulate the expression of some ER target genes has led to the hypothesis that ERRs and ERs control overlapping gene expression programs, and thus, that ERRs may play important roles in the development of breast cancer. Studies have suggested that increased activity of ERRs promotes metabolism characteristic of normal cells, whereas decreased ERR activity would favor metabolism characteristic of tumor cells. Interestingly, the levels of ERRs in primary human breast cancer samples have been associated with the risk of cancer recurrence, as well as the prognosis for patients. However, the extent to which altering ERR activity can affect breast cancer progression has never been determined. Our proposed research will test the relationship between ERRs and breast tumor growth, so as to establish the value of ERRs as possible targets for the treatment of breast cancer.

We will engineer human breast cancer cells with different levels or activity of ERRs, and compare the growth properties of these cells under different conditions. We will test the ability of cells to: (1) grow in a defined environment in cell culture conditions, (2) survive treatment with different chemotherapeutic agents that are used to treat breast cancer patients, and (3) form tumors and metastasize when transplanted in a mouse model system. These experiments will define to what extent changes in ERR levels or activity lead to changes in tumor growth properties. In addition, we will identify the types of metabolic genes whose expression is altered when we increase ERR activity. This will provide insights into the mechanisms by which ERRs alter tumor growth properties.

The ERR regulators have been proposed to be of prognostic value in breast cancer. However, no study has tested directly whether ERRs have a causal role in breast cancer progression, as we plan to do. Moreover, current efforts to alter the metabolism of cells (so as to restrict tumor growth) have focused on inhibitors of specific metabolic enzymes. The proposed work will determine the extent to which we can exploit the role of ERRs as global regulators of metabolism that control the expression of multiple enzymes, to affect breast tumor growth. Moreover, because the proteins under study are themselves regulated by environment signals (e.g. up regulated by fasting and exercise), the studies may reveal long suspected but hard to unravel mechanisms by which lifestyle (e.g. diet, physical activity) affects breast cancer.


Final Report (2008)

The three Estrogen-Related Receptors, (ERRα, ERRβ and ERRγ, are transcription factors that share significant sequence similarity with the Estrogen Receptors (ERs). This similarity has led to the hypothesis that ERRs and ERs control overlapping gene expression programs, and thus, that ERRs, like ERs, may play a role in breast cancer development and/or growth. Interestingly, the levels of ERRα and ERRγ in primary human breast cancer samples have been associated with the risk of cancer recurrence, as well as the prognosis for patients. However, the extent to which alterations in ERR activity can affect breast cancer progression has never been determined.

To determine the role of ERRs in breast cancer growth, metastasis and response to drugs, we generated human MDA MB 231 breast cancer cells with desired changes in ERR activity. Increases in ERR activity were achieved via overexpression of the transcriptional co-activators PGC-1α or PGC-1β, which are expressed at very low levels in parent MDA MB 231 cells and are known to activate endogenous ERRα, as well as via overexpression of ERRγ (also expressed at very low levels in the parent MDA MB 231 cells). All cells with increased ERRα/γ activity showed expected changes in gene expression and metabolic properties, demonstrating the successful increase of ERR-dependent cellular pathways. Cells with increased ERR activity showed no difference in their ability to grow and respond to chemotherapeutic drugs in vitro (cell culture studies) but were severely compromised in their ability to grow in vivo, when transplanted in the mammary fat pad of mice. Our findings demonstrate that selective changes in ERRα/γ activity severely impact the growth of breast tumors in animal models, and suggest that ERR ligands may have application in breast cancer treatment.

Our future studies focus on delineating the mechanisms by which PGC-1α, PGC-1β and ERRγ affect tumor growth and/or tumor properties, and extending the value of our findings in different breast cancer models. Completion of this work is essential for deciding the type of ERR ligands that may benefit breast cancer patients.