Vitamin D and Breast Cancer Prevention: Cell Death vs Growth

Institution: Lawrence Berkeley National Laboratory
Investigator(s): Valerie Weaver, Ph.D. -
Award Cycle: 1995 (Cycle I) Grant #: 1FB-0400 Award: $70,000
Award Type: Postdoctoral Fellowship
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease

Initial Award Abstract (1995)
Breast cancer occurs as a result of a transition of normal breast epithelial cell behavior to that of uncontrolled cell growth. A major factor in this transition is the gradual loss of the normal cellular balance between cell division and cell death. An important function of the genes in a normal breast cell is to control the appropriate time for the cell to die. Such cell death balances the growth which occurs due to normal cell division. In all non-menopausal women there is a sequential burst of cell division followed by a tightly controlled round of cell death with each menstrual cycle. We have found that the extracellular matrix (ECM, an interwoven network of proteins which is in contact with these breast epithelial cells and gives them strength and support) gives signals which provide information to these cells. Thus the ability of breast cells to respond correctly to these messages is critical for maintaining the normal cell balance. In breast cancer the genes of the breast epithelial cell are altered such that these cells are now unable to respond appropriately to breast tissue ECM-derived signals. There is reason to believe that the active compound of vitamin D may act on breast cells to regulate the genes required for this responsiveness. We hypothesize that vitamin D may re-establish the normal cell growth and death cycle and that these effects may be mediated through critical cell-ECM signals. Regardless of the mode of action, however, vitamin D may be effective in assisting with the prevention of both primary breast cancer and its recurrence following therapy.

We have access to a unique human breast cell line which mimics breast cancer progression as it happens in the body. In addition we have the expertise with a novel ECM assay which allows the reconstruction of the normal breast cell environment in culture. Using this system I will examine the ability of breast epithelial cells to respond appropriately to signals from the ECM as they undergo transition from normal to cancerous behavior. Emphasis will be placed on their ability to undergo appropriate cell death. After establishing when the critical changes occur in this transition, I will study the ability of vitamin D to rescue this aberrant behavior. Finally I will begin studies to determine what crucial factors are important for this altered responsiveness by isolating vitamin D-responsive genes. The validity of these results will be determined by using clinical samples of normal and cancerous human breast tissue. These results will have important consequences for understanding the development of both primary and recurrent breast tumors. They should also provide information for the development of better diagnostic techniques.

Final Report (1998)
Note: This grant was extended 9-months to complete the project.

The extracellular matrix (ECM) is the protein scaffolding that forms the immediate environment of a cell. The ECM has been shown to be an important regulator of normal cell behavior. Breast cancer therapies such as vitamin D have been shown to influence cells by controlling their growth and death and promoting their normal behavior. This may be due to their ability to help the cells to listen and respond properly to signals from the ECM. We previously reported that normal breast cells organize their own matrix, stop growing, turn off their basal cell death pathway and rearrange themselves to form breast-specific tissue structures in response to signal from the ECM. However, breast cancer cells are not able to respond properly to the ECM. We further showed that this loss of responsiveness occurred prior to the onset of cancer, suggesting that this was a critical step in the progression towards malignancy of the breast. Based on these results we predicted that treatments such as vitamin D, which have been reported to induce correct breast cell behavior, might be able to produce these effects by correcting this communication breakdown.

We have now determined that the tumorigenic HMT 3522 cells in our breast cancer progression series have abnormally elevated levels of a class of ECM-response elements (beta-1-integrins) and exhibit enhanced downstream signaling connected with these elements. Correction of this defect by treating these cells with integrin element function-blocking antibodies leads to the complete correction of growth and death control in these cells and promotes their breast tissue specific behavior. Most importantly these corrected cells now have a greatly reduced tumor potential in vivo. This clearly demonstrates that be rescuing how a breast tumor cell is able to communicate can prevent the expression of its malignant behavior.

We have determined that all of our cells within our progression series express vitamin D receptors. We report that treatment of tumor cells with vitamin D reduced the final cell number with maximal effects at 5OnM. Studies are now underway to determine if these effects are due to the alteration of cell/ECM interactions and the induction of cell death. These studies will be expanded to include the effect of vitamin D on the various precancerous cell passages.

Extracellular matrix and nuclear matrix interactions may regulate apoptosis and tissue-specific gene expression: a concept whose time has come
Periodical:Advances in Molecular and Cell Biology
Index Medicus:
Authors: Weaver VM, Lelievre S, Larabell CA, and Bissell MJ
Yr: 1997 Vol: 24 Nbr: Abs: Pg:1-55

Differentiation and cancer in the mammary gland: Shedding new light on an old dichotomy
Periodical:Advances in Cancer Research
Index Medicus:
Authors: Weaver VM, Petersen OW, Ronnov-Jessen l,and Bissell MJ
Yr: 1997 Vol: 75 Nbr: Abs: Pg:135-161

Structural cues from the tissue microenvironment are essential determinants of the human mammary epithelial cell phenotype
Periodical:Journal of Mammary Gland Biology and Neoplasia
Index Medicus: J Mammary Gland Biol Neoplasia
Authors: Weaver VM, Schmeichel KL, and Bissell MJ
Yr: 1998 Vol: 3 Nbr: 2 Abs: Pg:201-213

Reversion of the malignant phenotype of human breast cells in 3-dimensional culture and in vivo by integrin blocking antibodies
Periodical:Journal of Cell Biology
Index Medicus: J Cell Biol
Authors: Weaver VM, Petersen OW, Wang F, Larabell CA, Briand P, Damsky C, and Bissel MJ
Yr: 1997 Vol: 137 Nbr: 1 Abs: Pg:231-245

Extracellular matrix: the central regulator of cell and tissue homeostasis
Periodical:Trends in Cell Biology
Index Medicus: Trends Cell Biol
Authors: Weaver VM and Roskelly CD
Yr: 1997 Vol: 7 Nbr: Abs: Pg:40-42

The importance of the microenvironment in breast cancer progression: recapitulation of mammary tumorigenesis using a unique human mammary epithelial cell model and a 3-dimensional culture assay
Periodical:Journal of Biochemistry and Cell Biology
Index Medicus: J Biochem Cell Biol
Authors: Weaver VM, Fischer AH, Peterson OW, and Bissel MJ
Yr: 1997 Vol: 74 Nbr: Abs: Pg:833-851

Tissue structure, nuclear organization and gene expression in normal and malignant breast
Periodical:Cancer Research
Index Medicus: Cancer Res
Authors: Bissell MJ, Weaver VM, Lelievre SA, Wang F, Petersen OW, and Schmeichel KL
Yr: 1999 Vol: 59 Nbr: 7 Suppl Abs: Pg:1757-1764s

Functional culture models for studying mechanisms governing mammary epithelial cell apoptosis in normal and malignant breast
Periodical:Journal of Mammary Gland Biology and Neoplasia
Index Medicus: J Mammary Gland Biol Neoplasia
Authors: Weaver VM, Bissell MJ
Yr: 1999 Vol: 4 Nbr: 2 Abs: Pg:193-201