Cripto-A Breast Cancer Marker?

Institution: The Burnham Institute for Medical Research
Investigator(s): Christina Niemeyer, Ph.D. -
Award Cycle: 1995 (Cycle I) Grant #: 1FB-0064 Award: $75,600
Award Type: Postdoctoral Fellowship
Research Priorities
Detection, Prognosis and Treatment>Imaging, Biomarkers, and Molecular Pathology: improving detection and diagnosis

Initial Award Abstract (1995)
The purpose of this project is to study ‘Cripto’, a protein produced at elevated levels in a majority of human breast cancer cells but not in normal breast cells. Cripto is a growth factor for breast cells and can cause morphological changes. Thus, it is a good candidate for a breast cancer marker and could be used in the earlier detection of the threat of cancer. However, very little is known about its role in mammary gland development and during the various stages of breast carcinogenesis. Before any marker for mammary carcinogenesis can be used in early detection strategies, prior knowledge of its mode of activation is essential. Also important is determining how it can be detected. The long-term objectives of this project are to determine the role Cripto plays in mammary gland carcinogenesis and to ascertain its use as a diagnostic marker for breast cancer. Knowledge gained from this study of Cripto will also open an avenue for prevention strategies.

Questions, hypotheses, and methods: 1) Is the over- production of Cripto an initiation event or are the elevated levels observed later in tumorigenesis? The time course during various stages of tumor formation and progression will be studied in mice that produce mammary tumors caused by the over-production of oncogenes. Cripto activation possibly precedes the onset of cancer and therefore can be used as a marker of tumor-precursor cells. 2) Can chemical agents modulate Cripto production and thus the transforming ability of Cripto over- production? Cripto production is decreased by retinoic acid in certain cells. The effect of clinical treatment agents such as retinoids, tamoxifen, and selenium will be assayed. 3) Does over-production of Cripto in mammary cells lead to abnormal mammary growth and does it act with other known oncogenes? Cripto will be over- and under- produced in a mammary cell culture to test the effect of aberrant Cripto production on cultured mammary cells' potential to become tumorigenic or grow abnormally. Cells over-producing Cripto will be transferred into normal mouse mammary fat pads and the cells allowed to develop into gland. The effect of Cripto on mammary development and the effect that components of the normal mammary gland have on Cripto over-producing cells will be tested. The question of whether Cripto acts synergistically with other known oncogenes will also be studied.

Final Report (1997)
Elevated levels of Cripto are detected in over eighty percent of breast carcinomas, whereas it is undetectable in normal human breast tissue, making it is a good candidate for a breast cancer marker. The goal of this project is to determine the molecular characteristics of Cripto in cancerous and normal mammary gland growth. We have previously shown that high levels of Cripto are observed during pregnancy and lactation when the breast undergoes extensive proliferation and several changes in its characteristics. A small amount of Cripto is observed in virgin mammary glands. Cripto is not detected following weaning of the young, when the mammary gland undergoes extensive remodeling and large scale programmed cell death. Cripto levels are not modulated by such agents as retinoids, tamoxifen, selenium, estrogen, or progesterone. Cripto amounts are, however, increased when the cells are grown in the presence of pregnancy hormones, hydrocortisone and prolactin. Aberrant levels of Cripto affect mammary cells in several ways: high levels of Cripto cause the cells to grow at an increased rate and to greater cell densities; decreased quantities of Cripto cause the cells to change morphology, grow more slowly, undergo programmed cell death at a higher rate, and become saturated at lower densities.

In the past year we have found that when "normal" mammary cells expressing elevated levels of Cripto are placed back into mouse mammary glands, they form abnormal outgrowths indicating Cripto does play a role in tumorigenesis. When tumor cells have one-fifth their normal Cripto amounts and are placed in the mammary gland they still produce tumors at the same rate and are histologically indistinguishable from the parental cells suggesting these cells were tumorigenic for reasons not relevant to Cripto levels. In transgenic mice with mammary tumors caused by the polyoma middle T gene, Cripto does not appear to be involved in the initiation of this cancer because high levels are observed only after tumor formation. Cripto is thus a growth factor for normal breast cells and when levels are elevated stimulate excessive cell proliferation at the expense of cell interactions important for their normal function. Future studies include: assaying Cripto during various stages of tumor formation and progression using transgenic mice with mammary tumors caused by known cancer genes; studying the effect of Cripto on the invasive properties of tumor cells; constructing and studying transgenic mouse lines that have elevated levels of Cripto in the mammary gland.

Decreased Egr-1 expression in human, mouse and rat mammary cells and tissues correlates with tumor formation
Periodical:International Journal of Cancer
Index Medicus: Int J Cancer
Authors: Huang RP, Fan Y, de Belle I, Niemeyer C, Gottardis MM, Mercola D, Adamson ED
Yr: 1997 Vol: 72 Nbr: 1 Abs: Pg:102-109

Cripto: roles in mammary cell growth, survival, differentiation, and transformation.
Periodical:Cell Death and Differentiation
Index Medicus: Cell Death Diff
Authors: C.C. Niemeyer, M.G. Persico, E.D. Adamson.
Yr: 1998 Vol: 5 Nbr: Abs: Pg:440-449

Preneoplastic mammary tumor markers: Cripto and Amphiregulin are overexpressed in hyperplastic stages of tumor progression in transgenic mice.
Periodical:International Journal of Cancer
Index Medicus: Int J Cancer
Authors: C.C. Niemeyer, B. Spencer-Dene, J-X. Wu, and E.D. Adamson.
Yr: 1999 Vol: 81 Nbr: Abs: Pg:588-591