DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Exploring the Role of Senescence and Its Associated Secretory Program to Breast Cancer and Aging

Principal Investigator: ELLEDGE, STEPHEN
Institution Receiving Award: BRIGHAM AND WOMEN'S HOSPITAL, INC.
Program: BCRP
Proposal Number: BC142212
Award Number: W81XWH-15-1-0711
Funding Mechanism: Breakthrough Award Funding Level 2
Partnering Awards:
Award Amount: $1,174,402.00


PUBLIC ABSTRACT

The incidence of breast cancer rapidly increases with age. The aging process is the biggest risk factor for breast cancer incidence and also impacts survival. One explanation for this is that cells accumulate mutations over time and mutations drive cancer. Another is that as we age, our immune system decreases in efficiency, which can allow cancers to more easily evolve. Another important aspect of aging relevant to breast cancer is changes in the microenvironment. Breast tumors dependent on the normal cell environment in the breast to grow, especially in the early stages of cancer development. Some such environments make tumorigenesis more favorable. Age is an important variable that promotes a pro-carcinogenic tissue environment. How that happens is not known, but if we could limit the impact of age, we could prevent or delay breast cancer onset.

A key change in the breast micro-environment during aging is the accumulation of senescent cells. Senescent cells are cells that experience DNA damage or activated oncogenes and that turn into a permanently arrested state that is still metabolically active and can live for years in this arrested state. This prevents cancer, and the genes controlling the process are well-known tumor suppressor genes such as p16 and p53. As we age, cells experience more DNA damage, in part because our telomeres shorten and look like DNA damage but also due to oxygen in the atmosphere. Thus, as we age more senescent cells accumulate. One of the properties senescent cells have is that they secrete things into their environment like proteins called cytokines and chemokine. These secreted proteins are what is call SASP, the senescence associated secretory phenotype, which is an inflammatory response that attracts the immune system. While that is good when we are young, when we get old, it is too much of a good thing and we have a chronically more inflammatory cellular environment. Senescent cells are known to promote tumor growth and to promote aging. In fact, one study in which cells were engineered to die when they became senescent prevented aging in the mouse. The promotion of aging and tumorigenesis by senescent cells is thought to be mediated by the SASP, but this has never been tested.

My lab discovered a key regulator of SASP called GATA4. GATA4 is turned on during senescence and activates SASP. By turning it off, we can block SASP without blocking cell cycle arrest. In this grant, we propose to use this information to experimentally test whether induction of SASP in human mammary cells alone can promote breast cancer. We will induce SASP by GATA4 expression or remove GATA4 from cells and establish whether those cells change their abilities to promote growth and establishment of breast cancer. We will test the same ideas in mice by deleting GATA4 from the breast to see if it changes the tumorigenic environment of cells. Having discovered this pathway, we now have designed cells that glow green when SASP is turned on by GATA4 during senescence. We propose to look for chemicals that block cells ability to glow green and thereby block establishment of the SASP. Being able to block SASP with a small molecule could be very important in reducing inflammation and blocking the increased incidence of breast cancer during aging.

These proposed studies will enhance our understanding of the effects of aging on the development of breast cancer. In addition, since chemotherapy used to treat primary breast cancers also induces senescence and SASP, this could in part explain the induction of secondary cancers in response to cancer treatments. Thus, understanding this pathway and being able to manipulate it to inhibit SASP during chemotherapy could impact rates of breast cancer recurrence due to chemotherapy in women with breast cancer.