Understanding Aging Effects in the Breast

Institution: Lawrence Berkeley National Laboratory
Investigator(s): Ana Krtolica, Ph.D. -
Award Cycle: 2002 (Cycle VIII) Grant #: 8KB-0100 Award: $448,730
Award Type: New Investigator Awards
Research Priorities
Biology of the Breast Cell>Biology of the Normal Breast: the starting point



Initial Award Abstract (2002)
Most cells from higher organisms, including humans, do not divide indefinitely. After certain number of cell divisions cells permanently stop proliferating. In addition, cells damaged by radiation, oxidative stress and other agents may also permanently stop growing. This permanent arrest in cell growth is termed cellular senescence. Senescent cells accumulate with age in humans. One of the consequences of cellular senescence is that senescent cells change some of their characteristics. For example, cells present in the fibrous matrix that surrounds many tissues and organs (stromal fibroblasts), upon reaching senescence, start degrading the tissue matrix rather than producing it. This can stimulate near-by cells to proliferate.

The number of breast cancer cases rises dramatically with age. We have proposed that cellular senescence contributes to this age-related rise in cancer because senescent fibroblasts (cells present in the tissue matrix) create a more permissive tissue environment for the development of cancer. We will investigate which particular mutations in breast cells make them sensitive to senescent fibroblasts and are therefore, critical for age-related breast cancer development.

To test the idea that senescent fibroblasts (cells present in the tissue matrix) create a more permissive tissue environment for the development of cancer, we have developed cell culture models in which we can study the effects of senescent cells on breast characteristics. We plan to use these models to measure the ability of breast cells with specific mutations to grow and become aggressive when stimulated by senescent fibroblasts. In this way we will explore how age-related changes in cellular environment influence mutated breast cells and stimulate them to develop into cancer.

This study seeks to fill a gap in our knowledge of cellular events involved in an understudied aspect of breast cancer - the contribution of age-induced changes in tissue environment to cancer development. In this proposal, we will establish how changes in the environment induced by aging and/or tissue damage can work together with the changes within the breast cell itself (mutations) to promote the transformation of a normal cell into a cancer cell.

In the long term, understanding the role changes in tissue environment, such as accumulation of damaged and senescent cells during aging, may have in development of breast cancer is crucial for formulating rational breast cancer prevention and treatment. For example, decisions on how to treat a patient may be influenced by the extent to which breast tissue environment is modified. In addition, it is possible to envision strategies aimed at selectively reversing or preventing changes in the tissue matrix caused by senescent cells.


Final Report (2006)
Most cells from higher organisms, including humans, do not divide indefinitely. After certain number of cell divisions cells permanently stop proliferating. In addition, cells damaged by radiation, oxidative stress and other agents may also permanently stop growth. This permanent arrest in cell growth is termed cellular senescence. Senescent cells accumulate with age in humans. One of the consequences of cellular senescence is that senescent cells change some of their characteristics. For example, cells present in the fibrous matrix that surrounds many tissues and organs (stromal fibroblasts), upon reaching senescence, start degrading the tissue matrix rather than producing it. This can stimulate near-by cells to proliferate.

The number of breast cancer cases rises dramatically with age. We have proposed that cellular senescence contributes to this age-related rise in cancer because senescent fibroblasts (cells present in the tissue matrix) create a more permissive tissue environment for the development of cancer. We investigated which particular mutations in breast cells make them sensitive to senescent fibroblasts and are therefore, critical for age-related breast cancer development.

We have introduced mutations into breast cells which make them more sensitive to senescent fibroblasts and tested whether senescent breast cells stimulate other breast cells to grow. We have entirely addressed the questions we proposed in Aim 1. We have extended our results by addressing the Aim 2 in which we unraveled the mechanisms of senescent fibroblast-induced abnormal proliferation and invasiveness and disruption of normal mammary differentiation. We have identified the molecules involved in this process and determined their relative contribution to the observed phenotype. We have performed animal studies proposed in Aim 3.

This study seeks to fill a gap in our knowledge of cellular events involved in an understudied aspect of breast cancer the contribution of age-induced changes in tissue environment to cancer development. In this proposal, we established how changes in the environment induced by aging and/or tissue damage can work together with the changes within the breast cell itself (mutations) to promote the transformation of a normal cell into a cancer cell. We have identified some of the factors produced by senescent fibroblasts that contribute to the changes we have observed. We are continuing to identify molecules responsible for the effects of aging/damaged tissue on the breast. These could be used as potential therapeutic targets for drug design.


Symposium Abstract (2003)
The number of breast cancer cases rises dramatically with age. Our goal is to establish how age-related changes in breast tissue contribute to this rise. We have proposed that cells which have permanently lost their ability to grow and reside in the aging tissue matrix (stroma), create a more permissive tissue environment for the development of cancer.

We now show that inactivation of specific genes in breast cells sensitizes them to the effects of aging stroma. Our results suggest that the permanently arrested stromal cells in aging breast tissue may promote growth only of the near-by breast cells harboring certain mutations. We hypothesize that permanently arrested stromal cells in this way contribute to the development of breast cancer in elderly.

This study seeks to fill a gap in our knowledge of cellular events involved in an understudied aspect of breast cancer - the contribution of age-induced changes in tissue environment to cancer development. In the long term, understanding the role changes in tissue environment, such as accumulation of permanently arrested stromal cells during aging, may have in development of breast cancer is crucial for formulating rational breast cancer prevention and treatment. For example, decisions on how to treat a patient may be influenced by the extent to which breast tissue environment is modified. In addition, it is possible to envision strategies aimed at selectively reversing or preventing changes in the tissue matrix caused by permanently arrested stromal cells.

Cancer and Aging: A Model for the Cancer Promoting Effects of the Aging Stroma
Periodical:International Journal Biochemistry and Cell Biology
Index Medicus: Int J Biochem Cell Biol
Authors: Krtolica A, and Campisi J
Yr: 2002 Vol: 31 Nbr: 11 Abs: Pg:1401-14

Quantification of Epithelial Cell Proliferation in Co-culture with Fibroblasts by Fluorescent Image Analysis
Periodical:Cytometry
Index Medicus: Cytometry
Authors: Krtolica A, Solorzano CO, Locket S, and Campisi J
Yr: 2002 Vol: 49 Nbr: 2 Abs: Pg:73-82

Oxygen Sensitivity Severely Limits the Replicative Life Span of Murine Fibroblasts.
Periodical:Nature Cell Biology
Index Medicus: Nat Cell Biol
Authors: Parrinello S, Samper E, Krtolica A, Goldstein J, and Campisi J
Yr: 0 Vol: 5 Nbr: 8 Abs: Pg:741-747

Integrating epithelial cancer, aging stroma and cellular senescence.
Periodical:Advances in Gerontology
Index Medicus: Adv Gerontology
Authors: Krtolica A, and Campisi J
Yr: 0 Vol: 11 Nbr: Abs: Pg:109-116

Reversal of human cellular senescence: roles of the p53 and p16 pathways
Periodical:Embo Journal
Index Medicus: EMBO J
Authors: Beausejour CM, Krtolica A, Galimi F, Narita M, Lowe SW, Yaswen P, and Campisi J
Yr: 0 Vol: 22 Nbr: 16 Abs: Pg:4212-4222

Aging and Stem Cells
Periodical:International Journal Biochemistry and Cell Biology
Index Medicus: Int J Biochem Cell Biol
Authors: Krtolica, A.
Yr: 0 Vol: 37 Nbr: 5 Abs: Pg:935-941

Senescent Fibroblasts Alter Differentiation and Promote Malignant Transformation of Mammary Epithelial Cells
Periodical:Journal of Cell Science
Index Medicus: J Cell Sci
Authors: Parrinello, S., Coppe, J.-P., Krtolica, A. and Campisi J.
Yr: 0 Vol: 118 Nbr: 3 Abs: Pg:485-496