Identifying Environmental Pollutants that Alter the Stress Response

EPA Grant Number: FP917797
Title: Identifying Environmental Pollutants that Alter the Stress Response
Investigators: de la Rosa, Rosemarie Michelle
Institution: University of California - Berkeley
EPA Project Officer: Lee, Sonja
Project Period: September 1, 2015 through August 31, 2018
Project Amount: $132,000
RFA: STAR Graduate Fellowships (2015) RFA Text |  Recipients Lists
Research Category: Academic Fellowships

Objective:

Stress activates the release of hormones called glucocorticoids (GC) that bind the glucocorticoid receptor (GR) and modulate the transcription of inflammatory genes in target immune cells. There is some evidence that known widespread mammary carcinogens are capable of altering GR signaling. This research proposes to determine if mammary carcinogens modify GR signaling in macrophages as well as their circulating precursors, monocytes, thereby altering cytokine production and promoting breast cancer development.

Approach:

Initially, I will use a receptor-based bioassay to screen for mammary carcinogens that alter GR signaling in vitro. Chemicals found to disrupt GR signaling will then be used to treat human monocyte cell lines in vitro and test for differences in GC sensitivity and cytokine secretion after stimulation. Lastly, I will use mice as an in vivo model to study how chronic exposure to mammary carcinogens alters monocyte GR signaling to promote breast cancer. I will determine the relationship between altered monocyte GR signaling and mammary tumor growth by transplanting tumor forming mouse breast cancer cells into treated and untreated control mice.

Expected Results:

This research project aims to discover breast cancer-related environmental chemicals that act through GR signaling. Chemicals that interfere with GR signaling are expected to impair GC-mediated suppression of pro-inflammatory cytokines secreted by stimulated monocytes. Monocytes isolated from mice exposed to mammary carcinogens, which alter GR signaling, are expected to exhibit greater pro-inflammatory cytokine secretion. This increase in inflammatory monocytes should enhance mammary tumor growth. Collectively, the results of this research will determine if GR signaling in monocytes is a potential mechanism by which environmental chemicals promote inflammation and breast cancer development.

Supplemental Keywords:

Glucocorticoid receptor, inflammation, breast cancer

Progress and Final Reports:

  • 2016
  • 2017
  • Final