Proton pump inhibitor use and risk of breast cancer, prostate cancer, and malignant melanoma: An Icelandic population‐based case‐control study

Abstract

Purpose Increased expression of Vacuolar‐type H+ ATPases (V‐ATPases), in the plasma membrane of cancer cells has been suggested to contribute to the development of aggressive cancer phenotypes by promoting acidic tumor microenvironments. Accumulating data suggest that proton pump inhibitors (PPIs) may elicit a chemopreventive effect via V‐ATPase inhibition in some cancers, but evidence is still limited. Therefore, we aimed to explore a potential preventive role of PPIs in this study. Methods In this population‐based case‐control study, we identified incident cases of breast cancer (n = 1739), prostate cancer (n = 1897), and malignant melanoma (n = 385) in Iceland between 2005 and 2014 from the Icelandic Cancer Registry. We assessed varying levels of PPI use through record linkages to the Icelandic Medicines Registry. For each case, we selected up to 10 age‐matched, sex‐matched, and calendar‐matched population controls using risk‐set sampling. Using conditional logistic regression, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) controlling for NSAID use. Results Adjusted ORs associated with ever use of PPIs were 1.03 (95% CI: 0.92‐1.16) for breast cancer, 1.12 (95% CI: 1.00‐1.25) for prostate cancer, and 0.84 (95% CI: 0.69‐1.12) for malignant melanoma. Analyses of high use of PPIs (≥1000 DDDs) yielded ORs of 0.97 (95% CI: 0.78‐1.19), 1.20 (0.99‐1.47), and 0.59 (0.40‐1.13) for breast cancer, prostate cancer, and malignant melanoma, respectively. Analyses of cumulative exposure to PPIs did not support a dose‐response relationship for any of the three cancer types. Conclusions Our findings do not support a chemopreventive effect of PPI use on breast cancer, prostate cancer, or malignant melanoma.

Association between Proton Pump Inhibitor Use and the Risk of Female Cancers: A Nested Case-Control Study of 23 Million Individuals

“…Previous studies have indicated the possible antitumor impacts of PPIs [ 42 , 43 , 44 ]. Second, PPI treatment inhibits proliferation of cancer by inhibiting V-ATPases residing in the plasma membrane, including intracellular acidification and alkalization of the tumor microenvironment, which have a chemopreventive impact [ 45 ]. Numerous in vitro and in vivo studies have investigated the impacts of V-ATPase activity on several cancers such as pancreatic, breast, cervical, and prostate cancers and malignant melanomas [ 19 , 41 , 45 , 46 , 47 ].…”

The Impact of Lifestyle on Prostate Cancer: A Road to the Discovery of New Biomarkers

“…Multiple medications have been studied for their role in PCa primary prevention, such as proton pump inhibitors (PPIs) [ 119 ], statins and NSAIDs [ 120 ], and secondary prevention, such as 5-AR inhibitors [ 121 ] and alpha-blockers [ 122 ].…”

“…PPIs are known to inhibit acid secretion and were originally developed to inhibit the extrusion of protons through H + /K + ATPases in stomach cells [ 123 , 124 ]. They have also been associated with a reduction in Vacuolar-type H + ATPase (V-ATPase) activity [ 119 ]. This reduced activity has been shown to have an anticarcinogenic effect in breast cancer [ 125 ], PCa [ 126 ], and melanoma [ 127 ].…”

“…This reduced activity has been shown to have an anticarcinogenic effect in breast cancer [ 125 ], PCa [ 126 ], and melanoma [ 127 ]. However, recent studies have not demonstrated a chemopreventive effect of PPIs in PCa [ 119 , 128 ].…”

Emerging insights on the role of V‐ATPase in human diseases: Therapeutic challenges and opportunities

“…Numerous in vitro and in vivo studies showed their anticancer effect in terms of tumor growth, carcinogenesis, and metastasis against different types of cancer models such as breast, colorectal, pancreatic, leukemia, among others (reviewed by 269–271 ). In humans, a population‐based case‐control study, which analyzed the use of PPIs in patients with breast cancer, prostate cancer, or melanoma in Iceland, concluded that the used of PPIs is not associated with reduced risk of these cancer types 272 . It is noteworthy though that the concentration of PPIs required to inhibit V‐ATPase is much higher than that used for gastric Na + /K + ‐ATPase, 273 which can partially explain the results of the previous study.…”