Biology of the Normal Breast
Biology of the Normal Breast Funding Data:
| Proportion of CBCRP's Total | ||
| Grants awarded in 2003: |
8 |
16% |
| Funded amount: |
$1,463,162 |
13% |
Biology of the Normal Breast Portfolio Summary:
The biology of the normal breast is a greatly understudied area. The breast is a complex structure composed of several cell types that function to generate milk or to support the cells that generate milk. We know that the milk forming cells are the ones that are most likely to give rise to tumors, but there are many questions yet to be answered. How do the different types of cells interact in the breast under normal conditions? What normal changes are necessary for the breast to function properly? Without knowing the answers to these questions, it requires a leap of faith to be able to identify the abnormal changes associated with cancer.
What we do know about the breast is that it is an organ in constant flux. Researchers are finding that how the breast remodels itself under the influence of internal and external factors dictates how it functions. The production of milk depends on the maturity (differentiation) of the breast cells, which in turn is controlled by hormones and growth factors and the immediate environment of the cells, as well as the internal and external physical structure of the cells. The eight newly funded grants in the biology of the normal breast priority area investigate various pathways that contribute to breast cell growth, maturation, and death.
The earliest stage of embryonic breast development involves the migration of the breast epithelial cells to the location on the body where the breast will eventually form. Saverio Bellusci of the Childrens Hospital Los Angeles received a three-year RFA to investigate this process. He will study how the interactions between the growth factor FGF10 and the WNT gene family direct breast epithelial cell migration. Ultimately this research may give us insights into the metastatic process of breast tumors.
Three investigators were granted awards to study the regulation of gene activation and inactivation in the normal breast cell. First, John Conboy of the Lawrence Berkeley National Laboratory will use an IDEA award to investigate the changes in cell behavior due to “alternate splicing”—when one gene produces different proteins from the same code. Dr. Conboy will study the mechanism for the determining which protein is produced under different cellular conditions. Next, Peter Kaiser of the University of California, Irvine, will also use an IDEA award to study the genetic regulation of the breast cancer susceptibility gene BRCA1 through a process of protein degradation, called ubiquitylation. Finally, Yuehai Ke at The Burnham Institute was awarded a postdoctoral fellowship to determine the role of a set of proteins call tyrosine phosphatases, which are known to regulate the activation of other proteins, in the development and normal functioning of the mammary gland.
The aging of breast cells and supporting stroma results in changes that may contribute to breast cancer. Two newly funded CBCRP grants will investigate the role of DNA integrity in the function of normal breast cells. First, Kimberly McDermott of the University of California, San Francisco, will undertake a postdoctoral fellowship to investigate the how the cellular structures that regulate DNA replication (centrosomes) function to protect it from mutations and chromosomal abnormalities. Next, Paul Yaswen of the Lawrence Berkeley National Laboratory received a STEP award to investigate a newly discovered gene, called BORIS, for its role in controlling the integrity of DNA and to determine whether it plays a role in the early transformation of breast cells.
The early changes in the transition from a normal breast cell to a breast tumor cell are subtle, but it is the goal of two studies funded this year to define the key genetic changes in this transition. Thea Tlsty of the University of California, San Francisco developed an early precursor model of breast cancer, called the variant Human Mammary Epithelial Cell (vHMEC) that has specific genetic characteristics. Dr. Tlsty will determine whether these same characteristics can be found in early pre-cancer breast lesions, and therefore be used to distinguish them from normal breast tissue. Finally, the “information age” has opened new avenues for characterizing and understanding important changes to tissues at the protein level. One new technology is called “proteomics”, which is the simultaneous comparison of presence or absence of a panel of proteins in tissues under different physiological conditions. Dave Hoon, Armando Giuliano, and Lori Wilson (co-PIs) at the John Wayne Cancer Institute were awarded a Translational Research Collaboration Pilot Award (TRC pilot) to apply this new technology to the breast. The two major goals of the project are to: (1) determine whether it is possible to develop a proteomic profile “signature” of normal breast tissue during different stages of breast physiology, and (2) to determine if proteomic profile signatures of various types of breast lesions can be used to identify early pre-cancerous breast disease.
Biology of the Normal Breast Grants Funded in 2003:
FGF10 and Mammary Placode Induction in Mouse
Saverio Bellusci
Childrens Hospital, Los Angeles
Request for Applications Award
3 years; $446,400
Alternative pre-mRNA Splicing in Mammary Epithelial Cells
John Conboy
Lawrence Berkeley National Laboratory
IDEA
1.5 years; $122,542
Translational Proteomics of Normal to Benign Breast Disease
Dave Hoon, Lori Wilson & Armando Giuliano (co-PIs)
John Wayne Cancer Institute
Translational Research Collaboration—Pilot Award
1.5 years; $188,800
Identification of BRCA1 Ubiquitylation Targets
Peter Kaiser
University of California, Irvine
IDEA
1.5 years; $75,000
Dissection of Signaling Events in the Mammary Gland in vivo
Yuehai Ke
The Burnham Institute
Postdoctoral Fellowship Award
2 years; $86,400
Does Disregulaton of Centrosomes Cause Breast Cancer?
Kimberly McDermott
University of California, San Francisco
Postdoctoral Fellowship Award
2 years; $80,000
Early Transitions in Breast Cancer
Thea Tlsty
University of California, San Francisco
STEP Award
2 years; $199,999
Functional Analysis of BORIS, A Novel DNA-binding Protein
Paul Yaswen
Lawrence Berkeley National Laboratory
STEP Award
2 years; $264,021
