Breast cancer risk associated with phosphate toxicity

Abstract

Background - The essential dietary mineral phosphorus in the form of inorganic phosphate (PO43-) is regulated in the blood serum by a sensitive network of endocrine hormones released from bone, kidneys, parathyroid glands, and intestines. Western dietary patterns are high in phosphorus-rich foods, including dairy, meats, grain products, and foods processed with phosphate additives. Consequently, average phosphate intake is far above the U.S. dietary reference intake of 700 mg for adults. Phosphate toxicity, the accumulation of excess inorganic phosphate throughout the body from dysregulated phosphate metabolism, is associated with tumorigenesis as high levels of inorganic phosphate within the tumor microenvironment stimulate cell signaling pathways and promote cancer cell proliferation. Breast cancer in women is projected to increase to 3-million new cases globally by 2040, yet much of the public remains unaware that breast cancer is associated with alcohol consumption, and phosphate toxicity may play a mediating role in the association of alcohol with breast cancer. Phosphate toxicity is also associated with osteolytic loss of bone mineral density and abnormal osteoblastic bone mineral deposition.

Methods - This thesis presents three studies investigating the association of phosphate toxicity with risk of breast cancer in women related to alcohol consumption, high dietary phosphate intake, and disorders of spinal bone mineral density. A grounded theory literature-review method was used in the first study to retrieve research findings from the literature on alcohol, kidney function, phosphate metabolism, rhabdomyolysis, and breast cancer. Findings were compared and categorized into concepts and themes and were synthesized into a theory positing a mechanism by which the association of breast cancer with alcohol consumption is mediated by phosphate toxicity. The second study used a nested case-control design to measure the relative risk of breast cancer incidence associated with dietary phosphate intake levels in a cohort of middle-aged women from the Study of Women’s Health Across the Nation. The lowest level of 800 to 1000 mg phosphorus per day, based on recommendations from the United States National Kidney Foundation, was used as the reference level to calculate the relative risk of breast cancer in the higher levels of phosphorus intake. The third study used a mixed-methods grounded theory design to synthesize a theory relating phosphate toxicity with breast cancer and spinal bone mineral disorders. Based on the theory, the study used a mixed-effects model to test the hypothesis that changes in spinal bone mineral density are associated with incidence of breast cancer in women from the Study of Women’s Health Across the Nation.

Results - Results of the first study found that alcohol burdens renal function, which can impair the regulation of inorganic phosphate, reduce excretion of excess serum phosphate, and increase phosphate toxicity, a potential mediating factor in breast cancer risk. Alcohol can also cause nontraumatic rhabdomyolysis which ruptures cell membranes and releases inorganic phosphate, contributing to hyperphosphatemia (blood serum phosphate levels above 4.5 mg/dL) with increased breast cancer risk. Furthermore, phosphate toxicity potentially mediates the risk of cancer associated with kidney disease in the medical specialty of onco-nephrology. In the second study, the highest daily intake of dietary phosphorus in the cohort from the Study of Women’s Health Across the Nation, >1800 mg, is approximately equivalent to menus promoted by the United States Department of Agriculture. This level of dietary phosphorus was associated with a 2.3-fold increase in the risk of breast cancer incidence compared to the reference level of 800 to 1000 mg (RR: 2.30, 95% CI: 0.94–5.61, p = 0.07). The study’s clinically significant effect size, specificity, biological gradient, and other findings meet Bradford Hill’s criteria for causative inference from epidemiological associations. Randomized trials are warranted to test epidemiological associations of dietary components with reduced risk of cancer, as recommended by the National Cancer Institute The analysis of findings from the reviewed literature in the third study confirmed an association of phosphate toxicity with bone mineral disorders and tumorigenesis. In the follow-up study to test the hypothesis that bone mineral disorders are associated with tumorigenesis, women in the Study of Women’s Health Across the Nation who self-reported breast cancer were found to have higher bone mineral density at baseline. But these women also had more rapid losses in bone mineral density during follow-up visits compared to women in the control group who remained cancer free. These findings are consistent with osteolytic and osteoblastic bone mineral changes associated with breast cancer.

Conclusions - Thesis findings provide the rationale for further clinical studies to test dietary phosphate as a modifiable cause of breast cancer and bone mineral disorders. The effect of alcohol associated with phosphate toxicity can also be disseminated to the public to increase awareness of the risk of breast cancer associated with alcohol consumption.