Role of Id-2 in Breast Cancer and its Relationship to Id-1

Institution: California Pacific Medical Center Research Institute
Investigator(s): Pierre-Yves Desprez, Ph.D. -
Award Cycle: 2001 (Cycle VII) Grant #: 7WB-0026 Award: $296,531
Award Type: STEP Award
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease



Initial Award Abstract (2001)
Breast cancer develops as a result of loss of control mechanisms that are crucial for the development and function of the normal breast. The purpose of this proposal is to understand several important aspects of the molecular mechanisms responsible for the loss of growth control and gain of invasive function in breast cancer cells.

The focus of our investigation will be to study the role of a protein located inside of the cells called Id-2 in these important events in the breast. Id-2 is closely related to a protein we previously studied, Id-1. Our earlier studies demonstrated that the level of Id-1 in breast cells is very carefully controlled during the normal process of growth arrest and gain of function (milk production). When the level of Id-1 becomes too high, these cells begin to grow and invade uncontrollably (signs indicative of incipient cancer), and can no longer become functional and produce milk. More recently, we have obtained evidence that, in mouse breast, the amount of Id-2 is also critical to normal growth, but in the opposite direction of Id-1. That is, it seems that high levels of Id-2 protein are required for normal growth and function. So we believe that low levels of Id-1 and high levels of Id-2 are characteristic of healthy breast cells, while the opposite is true for aggressive cancerous cells. Therefore, based on our findings in cell culture systems and in the mouse mammary gland, we propose that changes in the level of Id-2 protein play a crucial role in breast cancer progression. We believe that the presence of high Id-2 levels is indicative of a good prognosis, and that Id-2 may be lost in cancer cells that spread from the original tumor (metastasis).

Aggressive, invasive breast cancer cells normally have low levels of Id-2. We will engineer these cells to produce high levels of Id-2, and determine the effects of these high levels on their invasive behavior. We predict that this behavior will be lost or reduced. We will also determine the effect of reducing levels of Id-2 in non-aggressive breast cancer cells. The prediction here is that these cells will become more aggressive, and develop the ability to spread to other organs.

Our previous work provided important insights into the regulatory mechanisms responsible for many aspects of normal breast development. This proposed work will reveal how the normal regulation may be lost in breast cancer progression, beginning with a localized tumor and developing to a tumor able to spread to other parts of the body. Our central hypothesis is that both Id-1 and Id-2 are involved in determining the fate of normal and transformed (incipiently cancerous) breast epithelial cells, through a coordinated expression of both proteins. Breast would represent the first organ in which the importance of this coordination of Id-1/Id-2 is established.


Final Report (2004)
The purpose of this proposal was to understand some important aspects of the molecular mechanisms responsible for the loss of growth control and gain of invasive function in breast cancer cells. Precisely, the focus of our investigation was to study the role of an intracellular protein, called Id-2, in these important events in the breast. Id-2 is closely related to a protein we previously studied, Id-1. We found that a decrease in Id-1 expression is necessary for growth arrest and gain of function in breast cells. More recently, we have obtained evidence that the amount of ld-2 is also critical, but in the opposite direction of Id-1. That is, high levels of ld-2 protein are required for growth arrest and gain of function.

We therefore proposed that changes in the level of ld-2 protein also play a crucial role in breast cancer progression. Aggressive and invasive breast cancer cells normally have low levels of ld-2. We therefore engineered these cells to produce high levels of Id-2, and we determined the effects of these high levels on their proliferative and invasive behavior. As predicted, this behavior was strongly reduced. Cell proliferation was decreased and cells lost the ability to invade. Furthermore, the level of secretion of degrading enzymes was reduced in these cells and cell-cell communications were re-established. Further we determined on several human tumor biopsies that Id-2 was absent in infiltrating and invasive tumors. So we believe that high levels of Id-2 are characteristic of non-aggressive breast cells.

Our previous work provided important insights into the regulatory mechanisms responsible for many aspects of normal breast development. This current work is now revealing how the normal regulation may be lost in breast cancer progression, beginning with a localized tumor and developing to a tumor able to spread to other parts of the body. Our central hypothesis is that both Id-1 and Id-2 are involved in determining the fate of normal and transformed (incipiently cancerous) breast epithelial cells, through a coordinated expression of both proteins. Breast would represent the first organ in which the importance of this coordination of Id-1/Id-2 is established.


Symposium Abstract (2003)
Breast cancer is thought to result from a multistep process. For a cancer cell to metastasize and spread, it has to acquire the ability to invade and to migrate from its original site, and to grow and divide in a new environment. The focus of our investigation is to study the role of intracellular proteins, called Id proteins, in these important events in the breast. We have found that when the levels of Id-1 (the first Id protein isolated) become too high in normal mouse mammary cells, these cells begin to grow and invade uncontrollably, and can no longer become functional and produce milk (1,2). Breast tumor biopsies from patients reveal that Id-1 protein is increased in infiltrating tumors as compared to localized tumors such as ductal carcinomas in situ (3). We determined the mechanisms responsible for constitutive Id-1 expression in invasive and meta-static breast cancer cells (4). We have also found that Id-1 is able to control the levels of several other proteins which are important in cell-cell communication, cell proliferation and in the spread of the tumor cells. Finally, we recently were able to prevent progression of breast cancer metastasis by using Id-1 as a molecular target (5).

We have obtained evidence that the amount of Id-2 (a protein closely related to Id-1) is also critical for the behavior of breast cells. However, unlike Id-1, high levels of Id-2 protein are required for growth arrest and gain of function in normal breast cells (6). Moreover, aggressive and invasive breast cancer cells have low levels of Id-2. We therefore engineered these cells to produce high levels of Id-2, and we determined that their proliferative and invasive behaviors were strongly reduced. We also determined that Id-2 producing cancer cells have lost the ability to spread in vivo. Further we determined on human tumor biopsies that Id-2 was absent in infiltrating tumors (7). So we believe that high levels of Id-2 are characteristic of non-aggressive breast cells.

This work provides important insights into the regulatory mechanisms responsible for many aspects of breast cancer development and progression. Our central hypothesis is that both Id-1 and Id-2 are involved in determining the fate of normal and transformed (incipiently cancerous) breast epithelial cells, through a coordinated expression of both proteins. Breast represents the first organ in which the importance of this coordination of Id-1/Id-2 is established.

References: (1) Desprez et al., Mol.Cell.Biol., 1998, 18:4577; (2) Singh et al., J.Biol.Chem., 2001, 276:11852; (3) Lin et al., Cancer Res, 2000, 60:1332; (4) Singh et al., Oncogene, 2002, 21:1812; (5) Fong et al., PNAS, final acceptance pending; (6) Parrinello et al., J.Biol.Chem., 2001, 276: 39213; (7) Itahana et al., Cancer Res, in revision. (Supported by CBCRP grants #1KB-0274, 3IB-0123, 5IB-0111, 7WB-0026)

Role of Id-2 in the maintenance of a differentiated and noninvasive phenotype in breast cancer cells.
Periodical:Cancer Research
Index Medicus: Cancer Res
Authors: Itahana Y, Singh J, Sumida T, Coppe JP, Parrinello S, Bennington JL, Desprez PY
Yr: 2003 Vol: 63 Nbr: 21 Abs: Pg:7098-7105

Id-1 as a molecular target in therapy for breast cancer cell invasion and metastasis.
Periodical:Proceedings of the National Academy of Sciences of the United States of America
Index Medicus: Proc Nat Acad Sci, U S A
Authors: Fong S, Itahana Y, Sumida T, Singh J, Coppe JP, Liu Y, Richards PC, Bennington JL, Lee NM,
Yr: 2003 Vol: 100 Nbr: 23 Abs: Pg:13543-13548

Reduction of human metastatic breast cancer cell aggressiveness on introduction of either form a or B of the progesterone receptor and then treatment with progestins.
Periodical:Cancer Research
Index Medicus: Cancer Res
Authors: Sumida T, Itahana Y, Hamakawa H, Desprez PY
Yr: 2004 Vol: 64 Nbr: 21 Abs: Pg:7886-7892

Id proteins in epithelial cells.
Periodical:Experimental Cell Research
Index Medicus: Exp Cell Res
Authors: Coppe JP, Smith AP, Desprez PY
Yr: 2003 Vol: 285 Nbr: 1 Abs: Pg:131-145

Helix-loop-helix proteins in mammary gland development and breast cancer.
Periodical:Journal of Mammary Gland Biology and Neoplasia
Index Medicus: J Mammary Gland Biol Neoplasia
Authors: Desprez PY, Sumida T, Coppe JP
Yr: 2003 Vol: 8 Nbr: 2 Abs: Pg:225-239

Id genes and proteins as promising targets in cancer therapy.
Periodical:Trends in Molecular Medicine
Index Medicus: Trends Mol Med.
Authors: Fong S, Debs RJ, Desprez PY
Yr: 2004 Vol: 10 Nbr: 8 Abs: Pg:387-392