Biology of the Breast Cell: The Basic Science of the Disease

We need to move beyond the static picture of breast cancer in current tumor cell lines and animal models. We need new research to understand the pre-neoplastic, causative events of the disease at the tissue, cell, and genetic levels. Disease progression and the heterogeneity seen in the clinic need clarification at the basic science level. We must better understand the genetic and molecular signatures of the disease to treat it effectively.

Two of CBCRP's Priority Issues are represented, and the funding data, portfolio summaries, and funded grants are presented in separate sections:

Biology of the Normal Breast: The Starting Point

Funding Data:

 

Proportion of CBCRP's Total

Grants awarded in 2002:

11

16%

Funded Amount:

$3,076,254

21%

Biology of the Normal Breast Portfolio Summary:

The biology of the normal breast is a greatly understudied area. That is why the CBCRP has continued to support this priority issue. 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 eleven newly funded grants in the Biology of the Normal Breast priority area investigate various pathways that contribute to breast cell growth, maturation, and death. These include the:

  • Influence of breast structure on growth and maturation
  • Influence of DNA structure on growth and cell growth and maturation
  • Role of non-milk producing cells in the breast
  • Mechanisms of action of hormones and internal factors in breast cells
  • Discrimination of normal early changes in the breast from abnormal ones

Several grants are examining how the non milk-producing cells and the environment that surround the milk-producing cells affect their behavior during growth, development, and aging. The role of cells such as those lining the blood vessels could affect breast cell growth potential. Longchuan Chen of the La Jolla Institute for Molecular Medicine received a one-year IDEA Award to determine whether blood vessel precursor cells can affect mammary cell growth. The extracellular matrix that surrounds the breast cells can also be a major factor in breast development. Jamie Bascom at the Lawrence Berkeley National Laboratory will use a one-year dissertation award to determine how an extracellular protein, called epimorphin, interacts with progesterone to influence breast development, while Aylin Rizki from the Lawrence Berkeley National Laboratory will use a two-year postdoctoral fellowship to determine the role of the extracellular matrix in protecting the milk-producing cells from DNA damage. Ana Krtolica, also at the Lawrence Berkeley National Laboratory, has a three-year new investigator award in which she will determine whether the age of fibroblasts—a type of breast cell that provides support for the milk-producing cells—effects the biological processes of the milk-producing cells. Steven Artandi of Stanford University is also going to study the affects of aging in the breast using a three-year RFA, but he will focus on the role of telomerase and telomere shortening in this process.

Several investigators will explore the role of hormones and growth factors on breast cell growth and breast development. Estrogen, progesterone, and prolactin have all been shown to regulate breast cell growth, but their process for doing so is still unclear. Three investigators will look at the effect of putative intermediate players in hormone growth regulation on breast growth by removing them from cells or adding excess amounts to cells. Shi Huang of The Burnham Institute will use a two-year STEP award to investigate the role of an estrogen-receptor related protein, called RIZ1, in mammary gland development; Richard Price, Jr. from the University of California, San Francisco, will use a two-year postdoctoral fellowship to investigate the effect of varying levels of estrogen receptor on mouse milk-producing cells; and Hee Kwang Choi at The Burnham Institute will use a two-year postdoctoral fellowship to investigate the effect of Rac/STAT5—a putative master switch for estrogen and prolactin action—on mammary growth. Cindy Wilson of the University of California, Los Angeles, will use a two-year STEP award to explore a slightly different aspect of normal mammary growth control. She will determine the effect of differing levels of the growth factor receptor called HER-2 on mammary growth inhibition.

An additional reason for studying normal breast biology is to devise ways to sort out normal changes in the breast from pre-cancerous changes. Two studies using different methods to advance this goal have been funded. James Ford and Sylvia Plevritis at Stanford University have been funded to perform a one-year Translational Research Collaboration pilot project, which will use MRI screening to detect changes in the breast and then genetic analysis to determine whether the normal structures can be differentiated from abnormal ones. Saira Mian of the Lawrence Berkeley National Laboratory will use a three-year RFA to develop statistical techniques to sort out which genetic changes in the breast are significant.

Biology of the Normal Breast Grants Funded in 2002:

Understanding Telomere Dynamics in the Breast
Artandi, Steven
Stanford University
Request for Applications (RFA) Award
3 years, $675,691

Role of Epimorphin and Progesterone in Breast Development
Bascom, Jamie
Lawrence Berkeley National Laboratory
Dissertation Award
1 year, $23,825

Defining a Role for Endothelial Precursor Cells in Breast
Chen, Longchuan
La Jolla Institute for Molecular medicine
IDEA Award
1 year, $199,174

Rac/STAT5 Signaling
Choi, Hee Kwang
The Burnham Institute
Postdoctoral Fellowship
2 years, $86,400

Genetic Alterations in MRI Screen-Detected Breast Lesions
Ford, James & Plevritis, Sylvia
Stanford University
Translational Research Collaboration, Pilot Award
1.5 years, $157,000

Steroid Receptor Coactivators in Mammary Gland Development
Huang, Shi
The Burnham Institute
STEP award
2 years, $394,020

Understanding Aging Effects in the Breast
Krtolica, Ana
Lawrence Berkeley National Laboratory
New Investigator
3 years, $448,884

Statistical Techniques for Breast Biology & Cancer Research
Mian, Saira
Lawrence Berkeley National Laboratory
Request for Applications Award
3 years, $794,368

Targeting Estrogen Receptors to Mouse Mammary Epithelium
Price, Jr., Richard
University of California, San Francisco
Postdoctoral Fellowship
2 years, $80,000

Effect of Breast Cell Environment on Repair of DNA Damage
Rizki, Aylin
Lawrence Berkeley National Laboratory
Postdoctoral Fellowship
2 years, $80,672

The Importance of Growth Inhibitory Signals in Normal Breast
Wilson, Cindy
University of California, Los Angeles
STEP Award
2 years, $150,000

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