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(#6) A novel animal model for determining the role of circadian timing in breast cancer development

Award Number: R01CA231122
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2019
PERIOD OF PERFORMANCE END DATE: 09/30/2024

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(#6) A novel animal model for determining the role of circadian timing in breast cancer development - Project Summary/Abstract The increased risk of breast cancer due to working nights or rotating shifts has been attributed to disruption of circadian rhythms, chronic sleep loss, nighttime light exposure, melatonin suppression, and chronic stress and fatigue. Because shift work can alter these variables simultaneously, human studies have been unable to determine the relative contributions of these variables to increased cancer risk. Several studies in rodent cancer models have purported to show that circadian rhythm disruption increases cancer progression. Unfortunately, all of the methods used to disrupt rhythms also produce chronic sleep loss, melatonin suppression, and increased stress hormones, each of which is capable of promoting tumor growth and proliferation. Therefore, the results of those animal studies cannot be strictly attributed to circadian disruption. To date, there is not a single animal study that has isolated the effects of circadian disruption on cancer without these confounds. We believe that a new animal model is needed to address this problem. We can eliminate these confounds and directly address the role of the circadian system in tumor development and progression by employing a new animal model, the circadian-arrhythmic Siberian hamster (Phodopus sungorus). This model was developed in our laboratory over the past 20 years and is uniquely suited for this project because circadian timing can be eliminated without impairing sleep or inducing stress. Circadian timing is eliminated by a single photic treatment that we have termed, the Disruptive Phase Shift (DPS) protocol. This protocol eliminates the need to ablate the SCN or alter gene expression, thus leaving the animals arrhythmic, but neurologically and genetically intact. Thus, we can directly evaluate the contribution of circadian disruption to tumor development and progression by completely shutting off circadian timing, and without impairing sleep or inducing stress. We have chosen to investigate the role of circadian disruption in a breast cancer model where tumors are induced by the carcinogen N-methyl-N-nitrosurea (NMU;; MNU). This is a widely used and well-established model of human breast cancer that works well in our hamsters. NMU is highly specific for mammary tissue and tumors can be induced by a single injection of the carcinogen. We propose to: 1) definitively establish whether the loss of circadian timing (without impairing sleep) increases tumor development, 2) determine whether melatonin suppression that accompanies circadian-arrhythmia increases tumor development, and 3) use a scheduled feeding paradigm to ameliorate the effects of circadian arrhythmia on tumor development.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = -$131 )
2025	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Biology Research	000	5	2/14/2025	NON-COMPETING CONTINUATION	-$131
														Subtotal = -$131

Issue Date FY: 2023 ( Subtotal = $565,048 )
2023	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Biology Research	000	5	3/8/2023	NON-COMPETING CONTINUATION	$565,048
														Subtotal = $565,048

Issue Date FY: 2022 ( Subtotal = $565,043 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Biology Research	000	4	3/30/2022	NON-COMPETING CONTINUATION	$565,043
														Subtotal = $565,043

Issue Date FY: 2021 ( Subtotal = $576,579 )
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Biology Research	000	3	3/11/2021	NON-COMPETING CONTINUATION	$576,579
														Subtotal = $576,579

Issue Date FY: 2020 ( Subtotal = $576,579 )
2020	2020	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Biology Research	000	2	3/10/2020	NON-COMPETING CONTINUATION	$576,579
														Subtotal = $576,579

Issue Date FY: 2019 ( Subtotal = $576,631 )
2019	2019	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Biology Research	000	1	3/13/2019	NEW	$576,631
														Subtotal = $576,631

Grand Total All Awards = $2,859,749

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(#6) A novel animal model for determining the role of circadian timing in breast cancer development

Award Number: R01CA231122

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/01/2019

PERIOD OF PERFORMANCE END DATE: 09/30/2024

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