Vitamin K2 fights Breast and some other cancers - many studies

1.7 X less likely to get breast cancer if have high Vitamin K2 intake - May 2021

Vitamin K intake and breast cancer incidence and death: results from a prospective cohort study
Clinical Nutrition, Volume 40, Issue 5, May 2021, Pages 3370-3378. https://doi.org/10.1016/j.clnu.2020.11.009
Kang Wang a b g, Qianxue Wu a, Zhuyue Li c, Michael K. Reger d, Yongfu Xiong e, Guochao Zhong f, Qing Li a, Xiang Zhang a, Hongyuan Li a, Theodoros Foukakis g h, Tingxiu Xiang b, Jianjun Zhang i, Guosheng Ren a b

Background & aims
Vitamin K prevents growth and metastasis of certain cancers, but there is little evidence regarding the association between dietary vitamin K and breast cancer incidence and death. We sought to examine whether intakes of total vitamin K, phylloquinone (vitamin K1) and menaquinones (MKs) (vitamin K2) may influence risks of breast cancer incidence and death in the US population.

Methods
Herein, 2286 breast cancer cases and 207 breast cancer deaths were identified during 702,748 person-years of follow-up. Cox regression and competing risk regression were used to estimate multivariable-adjusted hazards ratios (HRs) and 95% confidence intervals (95% CIs) by dietary vitamin K intake quintile (Q) for risk of breast cancer incidence and mortality.

Results
After adjustment for confounders, the total MK intake was associated with an increased risk of breast cancer (HR Q5 vs Q1, 1.26; 95% CI, 1.05 to 1.52; Ptrend, 0.01) and death from breast cancer (HR Q5 vs Q1, 1.71; 95% CI, 0.97 to 3.01; Ptrend, 0.04). Non-linear positive dose–response associations with risks of breast cancer incidence and death were found for total MKs intake (Pnon-linearity<0.05). No statistically significant associations were observed between the intake of total vitamin K and phylloquinone and breast cancer.

Conclusions
The present study suggests that total MK intake was associated with an altered risk of the occurrence and death of breast cancer in the general US population. If our findings are replicated in other epidemiological studies, reducing dietary intake of menaquinones may offer a novel strategy for breast cancer prevention.

66 References are online

8+ Vitamin D Life Vitamin K pages with CANCER in title

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Vitamin K: A novel cancer chemosensitizer - Jan 2022

Biotechnology and Applied Biohemestry https://doi.org/10.1002/bab.2312 publisher wants $12 to access the PDF
Sameena Gul, Muhammad Faisal Maqbool, Amara Maryam, Muhammad Khan, Hafiz Abdullah Shakir, Muhammad Irfan, Chaman Ara, Yongming Li, Tonghui Ma

Cancer incidences are growing rapidly and causing millions of deaths globally. Cancer treatment is one of the most exigent challenges. Drug resistance is a natural phenomenon and is considered one of the major obstacles in the successful treatment of cancer by chemotherapy. Combination therapy by the amalgamation of various anticancer drugs has suggested modulating tumor response by targeting various signaling pathways in a synergistic or additive manner. Vitamin K is an essential nutrient and has recently been investigated as a potential anticancer agent. The combination of vitamin K analogs, such as vitamins K1, K2, K3, and K5, with other chemotherapeutic drugs have demonstrated a safe, cost-effective, and most efficient way to overcome drug resistance and improved the outcomes of prevailing chemotherapy.
Published reports have shown that vitamin K in combination therapy improved the efficacy of clinical drugs by promoting apoptosis and cell cycle arrest and overcoming drug resistance by inhibiting P-glycoprotein. In this review, we discuss the mechanism, cellular targets, and possible ways to develop vitamin K subtypes into effective cancer chemosensitizers. Finally, this review will provide a scientific basis for exploiting vitamin K as a potential agent to improve the efficacy of chemotherapeutic drugs.

Chapter 29 - Prostate cancer and applications of vitamin K - 2020

https://doi.org/10.1016/B978-0-12-811907-5.00027-0

Vitamin K is well known for its role in the coagulation process. However, a plethora of studies suggest that the metabolic function of vitamin K extends beyond coagulation, such as in osteoporosis and atherosclerosis. An even more interesting fact is that the emerging studies support that the intake of vitamin K could be beneficial in managing various types of cancers including prostate cancer (PCa). Interestingly, higher levels of vitamin K2 and higher intake of this vitamin are correlated with reduced fatal PCa, and vitamin K2 deficiency status has been found in most men with aggressive PCa. With a one in seven risk of developing PCa within their lifetime, this is an encouraging discovery. In vitro research studies also support the notion that various forms of vitamin K (K2, K4, and K3) are effective against different types of PCas. This chapter is focused on the potential beneficial effects of vitamin K use for PCa treatment based on various epidemiological and experimental studies conducted to date.

New insights into vitamin K biology with relevance to cancer - Oct 2022

Trends in Molecular Medicine. Volume 28, Issue 10, October 2022, Pages 864-881, https://doi.org/10.1016/j.molmed.2022.07.002
JoEllen Welsh 1, Min Ji Bak 1, Carmen J. Narvaez 1

Phylloquinone (vitamin K1) and menaquinones (vitamin K2 family) are essential for post-translational γ-carboxylation of a small number of proteins, including clotting factors. These modified proteins have now been implicated in diverse physiological and pathological processes including cancer. Vitamin K intake has been inversely associated with cancer incidence and mortality in observational studies. Newly discovered functions of vitamin K in cancer cells include activation of the steroid and xenobiotic receptor (SXR) and regulation of oxidative stress, apoptosis, and autophagy. We provide an update of vitamin K biology, non-canonical mechanisms of vitamin K actions, the potential functions of vitamin K-dependent proteins in cancer, and observational trials on vitamin K intake and cancer.

Vitamin K: Body Pools and Function in Breast Cancer Joellen Welsh – 2023

PreventCancer – US Govt Funded Grants

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 γcarboxyglutamate 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 γcarboxylation 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.