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Vitamin K: Body Pools and Function in Breast Cancer

Award Number: R01CA258231
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/09/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Vitamin K: Body Pools and Function in Breast Cancer - PROJECT SUMMARY/ABSTRACT This proposal focuses on the divergent effects of the two major dietary forms of vitamin K on breast cancer. K vitamins act as cofactors for gamma-glutamyl carboxylase (GGCX), which post-translationally introduces γ- carboxyglutamate residues into proteins. Although most of the 17 known γ-carboxylated proteins function in coagulation and bone homeostasis, the presence of GGCX in most tissues (including mammary gland) suggests more extensive physiological roles for vitamin K. We have demonstrated that triple negative breast cancer (TNBC) cell lines express GGCX and produce γ-carboxylated proteins in response to vitamin K1 (phylloquinone), the major dietary form. In TNBC cells, K1 treatment enriches for the stem cell marker aldehyde dehydrogenase 1 (ALDH1) and promotes mammosphere formation. These data suggest that K1 sustains GGXC mediated γ- carboxylation to drive aggressive breast cancer phenotypes. Through analysis of genomic cancer datasets, we find that ~25% of breast tumors express GGCX and the vitamin K oxidoreductase (VKOR) genes required for its activity. Patients with such tumors have poorer survival than those whose tumors do not express these genes at high levels. Patients with this subtype of tumor would be candidates for therapies that limit K1 availability and/or inhibit GGCX. Surprisingly, we found that vitamin K2 (menaquinone-4), another naturally occurring form present in diet, does not stimulate γ-carboxylation or stem cell phenotypes in TNBC cells, but instead strongly suppresses cell growth, migration and energy metabolism. These provocative data indicate that K1 and K2 exert distinct effects on breast cancer cells, with K1 promoting and K2 suppressing aggressive phenotypes. We also found that expression of the vitamin K2 biosynthesis enzyme UbiA Prenyltransferase Domain Containing 1 (UBIAD1) is undetectable in TNBC, suggesting altered cellular handling of vitamin K. In Aim 1 we will dissect the effects of K1 and K2 in vitro, evaluate the role of UBIAD1 and conduct feeding studies to measure accumulation of K1 and K2 in TNBC xenografts and host mammary gland in relation to tumor growth. In Aim 2 we will determine whether deletion of GGCX from TNBC cells impacts γ-carboxylated protein synthesis and aggressive phenotypes in vitro and in vivo. Aim 3 will identify relevant γ-carboxylated GGCX substrate proteins that mediate the effects of K1. We anticipate that growth of tumors with high GGCX activity and low UBIAD1 will be stimulated by high dietary K1 and inhibited by high dietary K2. These findings would identify GGCX as an oncogene and the vitamin K pathway as a therapeutic target in a subset of patients with advanced breast cancer.


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 = $353,419 )
2025	2025	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Cancer Cause and Prevention Research	000	5	12/27/2024	NON-COMPETING CONTINUATION	$318,077
2025	2025	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Cancer Cause and Prevention Research	001	5	6/3/2025	NON-COMPETING CONTINUATION	$35,342
														Subtotal = $353,419

Issue Date FY: 2024 ( Subtotal = $335,749 )
2024	2024	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Cancer Cause and Prevention Research	000	4	1/26/2024	NON-COMPETING CONTINUATION	$318,077
2024	2024	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Cancer Cause and Prevention Research	001	4	4/18/2024	NON-COMPETING CONTINUATION	$17,672
														Subtotal = $335,749

Issue Date FY: 2023 ( Subtotal = $458,040 )
2023	2023	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Cancer Cause and Prevention Research	000	3	1/30/2023	NON-COMPETING CONTINUATION	$346,350
2023	2023	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Cancer Cause and Prevention Research	002	3	2/27/2023	SUPPLEMENT FOR EXPANSION	$0
2023	2023	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Cancer Cause and Prevention Research	001	3	2/7/2023	SUPPLEMENT FOR EXPANSION	$111,690
														Subtotal = $458,040

Issue Date FY: 2022 ( Subtotal = $456,595 )
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Cancer Cause and Prevention Research	002	2	4/25/2022	NON-COMPETING CONTINUATION	$28,156
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Cancer Cause and Prevention Research	000	2	2/1/2022	NON-COMPETING CONTINUATION	$316,752
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Cancer Cause and Prevention Research	001	2	2/4/2022	SUPPLEMENT FOR EXPANSION	$102,571
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Cancer Cause and Prevention Research	003	2	5/9/2022	SUPPLEMENT FOR EXPANSION	$9,116
														Subtotal = $456,595

Issue Date FY: 2021 ( Subtotal = $427,325 )
2021	2021	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Cancer Cause and Prevention Research	000	1	2/9/2021	NEW	$365,766
2021	2021	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Cancer Cause and Prevention Research	001	1	9/17/2021	SUPPLEMENT FOR EXPANSION	$61,559
														Subtotal = $427,325

Grand Total All Awards = $2,031,128

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Vitamin K: Body Pools and Function in Breast Cancer

Award Number: R01CA258231

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/09/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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