Steroid Receptor Coactivators in Mammary Gland Development

Institution: The Burnham Institute for Medical Research
Investigator(s): Shi Huang, Ph.D. -
Award Cycle: 2002 (Cycle VIII) Grant #: 8WB-0092 Award: $377,450
Award Type: STEP Award
Research Priorities
Biology of the Breast Cell>Biology of the Normal Breast: the starting point



Initial Award Abstract (2002)
Steroid hormone (estrogen) exposure is known to be a breast cancer risk for breast cancer. The understanding of breast cancer development remains poor and will require a better understanding of the biology of the normal breast. The cells in normal breast tissue and early breast cancers depend on estrogen (which acts through the estrogen receptor) for survival and growth; the receptor acts in the cell nucleus, stimulating the activity of growth and survival genes. Breast cells that do not get estrogen stop proliferating and die. This is why breast cancer is treated with drugs that block estrogen activity. However, estrogen activity is not fully understood and much work is done trying to optimize the drugs that are used to block its activity and to develop new drugs, especially ones that could be safely used to prevent breast cancer development.

We have discovered a new tumor suppressor gene, RIZ1, which may be an important co-factor of the estrogen receptor. The RIZ gene, or the function of the protein encoded by it, is frequently lost in human cancers, particularly in breast cancers. We have shown in mice bearing RIZ1-negative tumors of human origin that bringing back the RIZ1 gene by means of gene therapy suppresses tumor growth. Newest results indicate that RIZ1 is one of the molecules in the cell that the estrogen receptors work through in a cell. RIZ1 may be an enzyme that changes other proteins in the nucleus in so that genes respond more readily to the commands of the estrogen receptor. We propose in this application to determine whether RIZ1 is indeed important in normal breast function and whether RIZ1 really has that suspected enzymatic activity and how it works at the molecular level.

RIZ1-deficient mice will be examined for abnormality in mammary gland tissues. The analysis will employ histological and molecular methods to look at differences between RIZ1 mutant and control mice with regard to morphology and molecular markers of mammary tissues. We will also study the enzyme function of RIZ1 and its regulation by estrogen in breast cells by using molecular, cellular and biochemical methods.

The enzymatic function and the physiological role of the RIZ1 class of enzymes in estrogen receptor function in mammary glands remains poorly understood. Our research affords the opportunity to establish for the first time that such an enzyme plays an important role in the function of the normal breast. The new understanding of estrogen receptor activity that we hope to emerge from these studies may help in the development of new preventive and therapeutic drugs for breast cancer.


Final Report (2004)
Steroid hormone (estrogen) exposure is known to increase breast cancer risk. The understanding of breast cancer development remains poor and will require a better grasp on the biology of the normal breast. The cells in normal breast tissue and early breast cancers depend on estrogen (which acts through the estrogen receptor) for survival and growth; the receptor acts in the cell nucleus, stimulating the activity of growth and survival genes. Breast cells that do not get estrogen stop proliferating and die. This is why breast cancer is treated with drugs that block estrogen activity. However, estrogen activity is not fully understood and much work is being done trying to optimize the drugs that are used to block its activity and to develop new drugs, especially ones that could be safely used to prevent breast cancer development.

We discovered a new tumor suppressor gene, RIZ1, which may be an important co-factor of the estrogen receptor. The RIZ gene, or the function of the protein encoded by it, is frequently lost in human cancers, particularly in breast cancers. We have shown that in mice bearing RIZ1-negative tumors of human origin restoring the RIZ1 gene through gene therapy suppresses tumor growth. Our newest results indicate that RIZ1 is one of the molecules in the cell the estrogen receptors work through in a cell. RIZ1 may be an enzyme that changes other proteins in the nucleus so that genes respond more readily to the commands of the estrogen receptor. We proposed in this application to determine whether RIZ1 is indeed important in normal breast function and whether RIZ1 really has that suspected enzymatic activity and how it works at the molecular level.

We have accomplished the goals of our specific aims. We showed that target organs of mice deficient in RIZ1 exhibit decreased response to female sex hormones. RIZ1 interacted with SRC1 and p300, suggesting that the coactivator function of RIZ1 may be mediated by its interaction with other transcriptional coactivators. In the presence of estrogen, RIZ1 binding to estrogen target genes became less direct and followed the binding of ER to DNA and RIZ1 methyltransferase activity on H3-Lys 9 was inhibited, indicating de-repression may play a role in estrogen induction of gene transcription. Reducing RIZ1 level correlated with decreased induction of pS2 gene by estrogen in MCF7 cells. The data suggest that a histone methyltransferase is required for optimal estrogen response in female reproductive tissues and that estrogen bound ER may turn a transcriptional repressor into a coactivator.

This new understanding of estrogen receptor function may help in the development of new preventive and therapeutic drugs for breast cancer.