Task Space radiation-induced persistent estrogenic response and risk of breast cancer development
Last Published:  11/23/20 11:55:12 AM (Central)
Short Title: Radiation-Induced Estrogenic Response and Breast Cancer Risk
Responsible HRP Element: Space Radiation
Collaborating Org(s):
Funding Status: Planned-Funded - Task expected to be within budget
Procurement Mechanism(s):
Solicited
Aims:
Specific Aim 1. Quantitatively compare effects of simulated GCR dose rates on mammary
tumor incidence and grade in APCMin/+ and PTEN+/- tumor model. While we demonstrate
intestinal tumorigenesis is independent of space radiation dose rate and high dose rate protons
increased mammary tumorigenesis, effects of space environment relevant GCR dose rates on
mammary tumorigenesis are yet to be defined. Our working hypothesis is that space radiation
increases mammary tumor frequency and grade with reduce latency period for tumorigenesis
irrespective of dose rates. To test the hypothesis, we will use female APCMin/+ and PTEN+/- mice
to score mammary tumor frequency, measure tumor size, and assess tumor grade after low dose
rate (chronic) simulated GCR. Results will be compared to high dose rate (acute) GCR exposures
and acute g radiation exposure will be used as base line reference.

Specific Aim 2. Characterize GCR dose rate effects on PER in relation to mammary
tumorigenesis.

Aim 2A. Define roles of PER in space radiation-induced mammary tumorigenesis. We
found that exposure to high dose rate protons led to increased systemic and local estrogenic
response. However, it is not yet known how GCR dose rate relevant to space environment affects
estrogen and ERa levels, which are critical for mammary tumorigenesis. Our working hypothesis
is that high and low dose rate GCR triggers similar PER to promote mammary tumorigenesis.
First, we shall determine the extent of systemic PER by measuring estrogen and its metabolites
in serum and urine respectively. Second, we also determine the extent of local PER in mammary
glands by assessing ERa and breast cancer associated signaling pathways. Third, we will use
normal and ovariectomized mice to determine roles of space radiation-induced PER in mammary
tumorigenesis.

Aim 2B. Determine dose rate effects on estrogen synthesis and metabolism. Our working
hypothesis is that irrespective of dose rate GCR triggers sustained activation of estrogen
synthesis in ovaries to promote systemic PER that promotes local PER in mammary glands. Our
strategy is to irradiate normal and ovariectomized mice to determine whether ovarian synthesis,
and/or altered estrogen metabolism is the source of increased estrogen, and whether local PER in
mammary glands is dependent/independent of ovarian estrogen.

Aim 2C. Does space radiation-induced PER modulate immune response to promote
mammary tumorigenesis? Although we demonstrate increased tumor associated macrophage
(TAM) in high dose rate g radiation-induced tumors, we are yet to determine GCR dose rate
effects on immune cell responses (immunophenotype of tumor infiltrating cells) that are key
factors in breast cancer development. Our working hypothesis is that both high and low dose rate
GCR triggers tumor promoting T cell responses in mammary glands. Using isolated T cells from
mammary tumors and peripheral blood, we shall determine to what extent GCR dose rate alters i)
Treg cell response, ii) Th1/Th2 polarization balance, and iii) M1/M2 macrophage polarization.

Specific Aim 3. Determine roles of SERM in countering space radiation-induced PER and
mammary tumorigenesis in APCMin/+. This aim will test the hypothesis that blocking radiationinduced PER will reduce space radiation-induced mammary tumorigenesis. The strategy will be to treat mice with an SERM, which is FDA approved for breast cancer chemoprevention in both pre- and post-menopausal women, before exposure to whole-body irradiation and quantitatively and qualitatively assess PER and mammary gland tumorigenesis. This aim will test causal relationship between chronic GCR-induced PER and mammary tumorigenesis and compare the data with acute GCR and g-rays.

Specific Aim 4. Risk assessment of mammary tumorigenesis after space radiation exposure.
The overall hypothesis is that RBE of PER and mammary tumorigenesis between acute and
chronic GCR is similar but higher relative to g-rays. We further hypothesize that the differences
in RBE of tumorigenesis between GCR and g-rays will be reflected in carcinogenic precursor
signaling events thus providing a molecular foundation to tumorigenic risk estimates of space
radiation. This aim will use acquired quantitative and qualitative experimental data from Aim 1
to 3 to calculate RBE of mammary tumorigenesis, which can then be used to model human risk
estimation as well as risk mitigation.
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