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Investigating the role of Eya3 in the regulation of innate immune signaling cascades in Triple Negative Breast Cancer

Award Number: F30CA257215
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/13/2021
PERIOD OF PERFORMANCE END DATE: 01/12/2024

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Investigating the role of Eya3 in the regulation of innate immune signaling cascades in Triple Negative Breast Cancer - PROJECT SUMMARY/ABSTRACT: Triple Negative Breast Cancer (TNBC) is a subtype of breast cancer characterized by low or absent expression of the estrogen receptor and the HER2 growth factor receptor. TNBC has high rates of metastasis and an overall poor prognosis in large part due to a lack of targeted therapeutics for treating both localized and disseminated disease. The Eyes absent (Eya) family of proteins are transcriptional cofactors that possess both intrinsic tyrosine phosphatase and associated serine/threonine phosphatase activity, and this family of proteins has been shown to play important roles in normal development in mice and humans. In addition to their developmental roles, Eya proteins have also been implicated in promoting nearly all known hallmarks of cancer. Recent published work from the laboratory of my mentor, Dr. Heide Ford, demonstrated that Eya3 plays an important role in suppressing CD8+ T-cell function within TNBC tumors by downregulating expression of PD-L1, primarily through its threonine phosphatase activity, and preliminary data suggests that it may also play a role in regulating the expression of various cytokines/chemokines in this context. Activation of innate immune signaling cascades in tumor cells, such as NF-kB, and downstream cytokine/chemokine signaling, has been shown to promote tumor progression, immune evasion, and distant metastasis in a variety of tumor types, including breast cancer. In preliminary experiments, we observed that shRNA-mediated Eya3 knockdown (KD) in murine TNBC cells reduced expression of multiple cytokines and chemokines and reduced NF-kB activation in vitro, suggesting a strong regulatory role of Eya3 in these signaling cascades. Additionally, in vivo experiments suggest that Eya3 KD in murine TNBC cells greatly reduces primary tumor growth and spontaneous metastasis in immune-competent mouse models, and this change correlates with significant alterations in innate immune populations within the Eya3 KD tumors compared to their control counterparts. With these preliminary findings in mind, we hypothesize that Eya3 expression regulates an innate immune signaling axis in TNBC cells which alters chemokine/cytokine signaling in the tumor microenvironment and facilitates enhanced primary tumor growth and metastasis. Our aims are as follows: 1. To determine the contribution of Eya3-mediated induction of innate immune signaling in TNBC cells to tumor-initiated immune suppression, tumor growth, and metastasis and 2. To identify the mechanism of action by which Eya3 regulates innate immune signaling pathways in TNBC. These studies present an opportunity not only to investigate the important biology governing tumor cell crosstalk and mechanisms of immune subversion, but additionally will identify potential novel therapeutic targets for prevention or treatment of disseminated TNBC.


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 = -$3,628 )
2025	2023	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Cancer Research Manpower	000	3	11/27/2024	NON-COMPETING CONTINUATION	-$3,628
														Subtotal = -$3,628

Issue Date FY: 2023 ( Subtotal = $36,803 )
2023	2023	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Cancer Research Manpower	001	3	6/6/2023	NON-COMPETING CONTINUATION	$942
2023	2023	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Cancer Research Manpower	000	3	12/27/2022	NON-COMPETING CONTINUATION	$35,861
														Subtotal = $36,803

Issue Date FY: 2022 ( Subtotal = $35,661 )
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Cancer Research Manpower	001	2	5/30/2022	NON-COMPETING CONTINUATION	$516
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Cancer Research Manpower	000	2	1/10/2022	NON-COMPETING CONTINUATION	$35,145
														Subtotal = $35,661

Issue Date FY: 2021 ( Subtotal = $35,145 )
2021	2021	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Cancer Research Manpower	002	1	2/2/2021	NEW	$0
2021	2021	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Cancer Research Manpower	001	1	2/2/2021	NEW	$516
2021	2021	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Cancer Research Manpower	000	1	1/12/2021	NEW	$34,629
														Subtotal = $35,145

Grand Total All Awards = $103,981

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Investigating the role of Eya3 in the regulation of innate immune signaling cascades in Triple Negative Breast Cancer

Award Number: F30CA257215

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/13/2021

PERIOD OF PERFORMANCE END DATE: 01/12/2024

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