Does Disregulaton of Centrosomes Cause Breast Cancer?

Institution: University of California, San Francisco
Investigator(s): Kimberly McDermott, Ph.D. -
Award Cycle: 2003 (Cycle IX) Grant #: 9FB-0158 Award: $80,000
Award Type: Postdoctoral Fellowship
Research Priorities
Biology of the Breast Cell>Biology of the Normal Breast: the starting point



Initial Award Abstract (2003)
Normal breast cells, taken from breast tissue of healthy women, can be grown in a dish in the laboratory. During the life span of normal breast cells they go through a process called cell division. Prior to the completion of cell division the genetic material of the cell must be duplicated. This results in an old and new copy of the genetic material. Once the genetic material is duplicated the cell must separate the old and new genetic material to opposite sides of the cell. Following separation of the genetic material, the original cell divides into two cells. The centrosome is an important component of all cells. The function of the centrosome is to direct the separation of the genetic material. Normal breast cells have two centrosomes, found on opposite sides of the cell. The centrosomes function is to orchestrate where, when and how the old and new copies of genetic material are separated.

Unequal separation of the genetic material is an early step in the formation of breast cancer. We have identified a small fraction of the normal breast cells that do not separate the genetic material into two equal parts. We refer to these cells as variant breast cells. The studies described in this proposal are designed to determine why the genetic material is not separated equally in variant breast cells. Preliminary data demonstrates that variant breast cells have abnormal centrosome numbers (more than two). We hypothesize that abnormal centrosome numbers cause unequal separation of the genetic material.

1. Our laboratory has established the expertise needed to grow normal breast cells in the laboratory. In addition, we have collected large numbers of breast tissue samples from healthy women of diverse racial backgrounds that can be used for this study.
2. Because we can grow these cells in the laboratory, we have the advantage of being able to manipulate them to test our specific questions. We will use revolutionary techniques designed to manipulate the genetics of these cells.
3. Our laboratory has a powerful microscope that can be used to visually count the number of centrosomes per cell with out damaging the cells.

While extensive research has revealed important information about breast cancer cells when they have reached aggressive stages, little is known about the events responsible for progression through the earliest stages of breast cancer. Normal human breast cells grown in the laboratory provide an extraordinary opportunity to study these events. Understanding these events will allow us to differentiate between normal and pre-cancerous cells, which will allow us to identify pre-cancerous cells of the breast. In addition, studies focusing on specifically killing the variant breast cells may lead to uses in clinical prevention and therapy.


Final Report (2006)
Normal breast cells, taken from breast tissue of healthy women, can be grown in a dish in the laboratory. During the life span of normal breast cells they go through a process called cell division. Prior to the completion of cell division the genetic material of the cell must be duplicated. Once the genetic material is duplicated the cell must segregate the old and new copies of the genetic material to opposite sides of the cell.

Following this segregation of the genetic material, the original cell divides into two cells and each inherits one complete copy of the genetic material. The centrosome is an important component of all cells. Normal breast cells have two centrosomes. The function of the centrosome is to orchestrate where, when and how the old and new copies of genetic material are segregated during cell division.

Unequal segregation of the genetic material is believed to be an early step in the formation of breast cancer. We have identified a small fraction of the normal breast cells that do not segregate the genetic material into two equal parts. We refer to these cells as variant breast cells. The studies described in this grant are designed to determine why the genetic material is not separated equally in these variant breast cells. We hypothesize that events leading to abnormal numbers of centrosomes cause unequal segregation of the genetic material and play a role in the earliest stages of breast cancer formation.

We have determined that variant breast cells, in contrast to normal breast cells, have abnormal numbers of centrosome (greater than two). Further studies demonstrated that the loss of an important tumor suppressor protein called p16 is responsible for the acquisition of abnormal numbers of centrosomes. We also showed, that p16 normally maintains normal numbers of centrosomes through regulating an important cell cycle enzyme called Cdk2. Finally, we definitively demonstrate for the first time that abnormal centrosome numbers cause unequal segregation of the genetic material.

While extensive research has revealed important information about breast cancer cells when they have reached late and aggressive stages, little is known about the events responsible for progression through the earliest stages of breast cancer. Normal human breast cells grown in the laboratory provide an extraordinary opportunity to study these events. Our studies strongly suggest that loss of p16 and acquisition of abnormal numbers of centrosome numbers are early events in the progression to breast cancer. Understanding the earliest events leading to breast cancer will provide us with the necessary tools to detect pre-cancerous cells in the breast and target the specific killing of these pre-cancerous cells.


Symposium Abstract (2005)
The centrosome is the major microtubule nucleating center of the cell and is responsible for establishing the bi-polar spindle apparatus during mitosis. Centrosome number is tightly controlled during the cell cycle by the coupling of the centrosome duplication cycle to the DNA replication cycle. Increases or decreases in centrosome number are hypothesized to result in abnormal segregation of chromosomes and abnormal chromosome numbers (anueploidy). In this study, we examined normal human mammary cell populations and found that loss of p16INK4a function uncoupled the DNA replication cycle from the centrosome duplication cycle and resulted in cells with abnormal centrosome numbers. The role of p16INK4a in this checkpoint was unmasked by transient inhibition of DNA synthesis. Previous studies suggesting that centrosome abnormalities drive genomic instability have only correlated the presence of centrosome abnormalities with genomic abnormalities in transformed cells. In this study we used genomically normal, human diploid cells that have normal numbers of centrosomes, generated >2 centrosomes and then subsequently demonstrated, for the first time, that an increase in centrosome number plays a causal role in genomic instability.

p16(INK4a) prevents centrosome dysfunction and genomic instability in primary cells.
Periodical:PLoS Biology
Index Medicus: PLoS Biol
Authors: McDermott KM, Zhang J, Holst CR, Kozakiewicz BK, Singla V, Tlsty TD.
Yr: 2006 Vol: 4 Nbr: 3 Abs: Pg:e51