Breast cancer, alcohol, and phosphate toxicity

Alcohol consumption is associated with an increased risk of breast cancer, even at low alcohol intake levels, but public awareness of the breast cancer risk associated with alcohol intake is low. Furthermore, the causative mechanisms underlying alcohol's association with breast cancer are unknown. The present theoretical paper uses a modified grounded theory method to review the research literature and propose that alcohol's association with breast cancer is mediated by phosphate toxicity, the accumulation of excess inorganic phosphate in body tissue. Serum levels of inorganic phosphate are regulated through a network of hormones released from the bone, kidneys, parathyroid glands, and intestines. Alcohol burdens renal function, which may disturb the regulation of inorganic phosphate, impair phosphate excretion, and increase phosphate toxicity. In addition to causing cellular dehydration, alcohol is an etiologic factor in nontraumatic rhabdomyolysis, which ruptures cell membranes and releases inorganic phosphate into the serum, leading to hyperphosphatemia. Phosphate toxicity is also associated with tumorigenesis, as high levels of inorganic phosphate within the tumor microenvironment activate cell signaling pathways and promote cancer cell growth. Furthermore, phosphate toxicity potentially links cancer and kidney disease in onco‐nephrology. Insights into the mediating role of phosphate toxicity may lead to future research and interventions that raise public health awareness of breast cancer risk and alcohol consumption.


| INTRODUCTION
Fewer than half of the people responding to a 2019 survey on cancer awareness conducted by the American Institute for Cancer Research (AICR) were aware that cancer was linked to alcohol consumption (AICR, 2019).The AICR suggested that popular messages about alcohol's benefits for heart health may distract people from warnings that alcoholic beverages-beer, liquor, and wine-are a "clear and convincing cause of several cancers, including breast and liver cancers."Another recent survey found that less than 20% of women in breast screening programs knew that alcohol consumption is a modifiable risk factor for breast cancer (Agabio et al., 2021).
According to the World Health Organization (WHO), "Many people, including women, are not aware that breast cancer is the most common cancer caused by alcohol among women globally" (WHO, 2021).
Furthermore, because of alcohol's toxic effect on every organ as it passes through the body, WHO warned that there is no safe level of alcohol consumption, and WHO stated that the risk of breast cancer increases with each unit of alcohol consumed per day (WHO, 2021).Findings of a recent national survey of US adults highlighted "the need to educate U.S. adults about the alcohol-cancer link, including raising awareness that drinking all alcoholic beverage types increases cancer risk" (Seidenberg et al., 2023).Yet, specific pathophysiological mechanisms linking alcohol with cancer are underinvestigated.
Global cancer incidence related to alcohol consumption was estimated from an analysis of GLOBOCAN 2020 data by WHO's International Agency for Research on Cancer (IARC) (Rumgay et al., 2021).Cancer attributed to alcohol consumption accounted for 4.1% of all new cancer cases globally in 2020.At 10 g of alcohol per drink, daily alcohol consumption was classified as moderate (<20 g), risky (20-60 g), and heavy (>60 g).Heavy, risky, and moderate consumption of alcohol accounted for 46.7%, 39.4%, and 13.9% of new cancer cases, respectively.Lighter consumption of alcohol-up to 10 g a day-accounted for 41,300 new cancer cases.Furthermore, among potentially modifiable risk factors associated with the incidence of US cancer cases and deaths in 2014, alcohol intake ranked just behind cigarette smoking and excess body weight, accounting for 5.6% of cancer cases and 4% of cancer deaths (Islami et al., 2018).
A 2020 study from the US National Institute on Alcohol Abuse and Alcoholism (NIAAA) reported that alcohol use is increasing in US adult women but not in men-64% of females consume alcohol compared with 68% of males (White, 2020).Although women consume less overall alcohol than men, women are at greater risk of harm due to lower levels of body weight and body water, which increase women's susceptibility to toxic effects from higher concentrations of blood alcohol.Breast cancer is among the cancers associated with light alcohol consumption (Bagnardi et al., 2015), and each additional beverage consumed containing approximately 10 to 12 g of alcohol increases breast cancer risk in a dose-dependent manner by 2%-12% (Scoccianti et al., 2014).Dietary Guidelines for Americans: 2020-2025 defines heavy alcohol drinking for women as four or more drinks in 1 day or eight drinks in 1 week (dietaryguidelines.gov,2020).Of concern, a survey conducted during the COVID-19 pandemic found a 41% increase in alcohol consumption by US women, which may be related to increased anxiety and depression (Pollard et al., 2020).Furthermore, recurrence of breast cancer is associated with alcohol consumption, including low consumption levels, especially in postmenopausal women (Simapivapan et al., 2016).
Relatedly, phosphate toxicity, the damaging effect on organ systems from the accumulation of dysregulated inorganic phosphate (Pi) in the body, has been associated with tumorigenesis (Brown & Razzaque, 2018).Phosphate is normally regulated by the kidneys and other organs through a network of endocrine hormones (Section 3), but when kidney function is burdened, excessive amounts of Pi can accumulate in the tumor microenvironment and stimulate cancer cell growth through cell signaling pathways (Section 6).However, no studies in the research literature have examined a potential mechanism linking phosphate toxicity, breast cancer, and alcohol consumption.The rationale for identifying novel pathophysiological mechanisms is to provide new insights and directions for future research.The present theoretical paper proposes a plausible mechanism by which phosphate toxicity mediates the association of alcohol consumption with breast cancer.Dissemination of this knowledge may assist in raising public health awareness of breast cancer and other cancer risks associated with alcohol consumption.

| METHOD
The present theoretical paper used a "Grounded Theory Literature-Review Method" proposed by Wolfswinkel et al. (2013) to rigorously and objectively select and analyze findings from the research literature in the investigation of phosphate toxicity, breast cancer, and alcohol.Grounded theory (GT) was originally developed in 1967 by sociologists Glaser and Strauss to bring a higher standard of quality and rigor to qualitative research (Chun Tie et al., 2019).GT has also been utilized in quantitative research (Chun Tie et al., 2019) and in mixed methods-GT (MM-GT) (Howell Smith et al., 2020).Using an iterative process of data collection and constant comparative analysis, GT enables researchers to construct a theory through induction, a method of discovering a principle from a set of data (Chun Tie et al., 2019).However, unlike data collection in traditional GT, the GT literature-review method in the present paper used published research findings as the exclusive source of data for synthesizing new knowledge linking alcohol consumption with breast cancer.
Beginning with purposeful sampling, which selects sources rich in information for deeper understanding of an unknown subject (Palinkas et al., 2015), the present study searched Google, Google Scholar, Pub Med, and Scopus using keywords, including breast cancer, alcohol, dysregulated phosphate, and phosphate toxicity.
Additional keywords were obtained from retrieved studies as the trail of evidence was followed, and all data sources relevant to the subject were considered without restrictions on date, type, or number of sources.
Pathophysiological mechanisms and epidemiological concepts obtained from research findings were sorted into categories and themes through comparative analysis.Themes were synthesized into causative, associative, and mediating epidemiological relationships (Brown, 2020a).As the theory began to emerge, additional data were collected through theoretical sampling to fill in knowledge gaps (Chun Tie et al., 2019).Data collection continued until theoretical saturation was reached, at which point where new knowledge was no longer obtained through analysis.The GT proposed in the present paper introduces a novel mechanism by which phosphate toxicity mediates the association of alcohol consumption with increased breast cancer incidence.Insights and perspectives from this GT may inform hypotheses for further research and help raise awareness of the breast cancer risk associated with alcohol.

| ENDOCRINE REGULATION OF PHOSPHATE
The dietary mineral phosphorus, often found in chemical combination with oxygen as a Pi anion (PO4 3À ), is an essential micronutrient with a dietary reference intake (DRI) of 700 mg/day for adults (IOM, 1997).
Phosphorus is the second most abundant mineral in the human body next to calcium, and Pi is found in combination with calcium as hydroxyapatite, the calcium phosphate compound in bone.Serum Pi is regulated by endocrine hormones from an axis formed by bone, kidney, parathyroid glands, and intestines, as shown in Figure 1 (Brown, 2020c).Pi absorption in the intestines is increased by the kidneys through the biosynthesis of activated vitamin D3, 1,25-dihydroxyvitamin D, also known as calcitriol, converted from the storage form of vitamin D3, 25(OH)D3.Fibroblast growth factor 23 (FGF23), released from osteocytes in bone, and parathyroid hormone (PTH), released from the parathyroid glands, inhibit kidney reabsorption of Pi and increase phosphaturia.Hyperphosphatemia stimulates the release of FGF23, which suppresses kidney biosynthesis of calcitriol (Torres & De Brauwere, 2011).Additionally, PTH increases the resorption of calcium from bones, and the kidneys and the brain release α-klotho, a cofactor with FGF23.Excess calcium phosphate formed in the blood serum from dysregulated phosphate metabolism can lead to ectopic calcifications deposited throughout soft tissue (Brown & Razzaque, 2015).Importantly, any factors that burden renal function can contribute to dysregulated phosphate metabolism and cause an abnormal rise of serum Pi levels in hyperphosphatemia.The following sections explain how alcohol burdens kidney function and causes nontraumatic rhabdomyolysis, leading to high serum levels of dysregulated Pi associated with an increased risk of breast cancer.

| ALCOHOL CARCINOGENICITY AND DYSREGULATED PHOSPHATE
A Monograph Working Group of the IARC in 2007 declared that alcoholic beverages were carcinogenic (Baan et al., 2007), although the exact causative mechanisms remain unclear.Current hypotheses of cancer-causing mechanisms include ethanol's impairment of tumor cell destruction by natural killer cells, activation of cell proliferation related to estrogen, and the carcinogenic effects of alcohol metabolites such as acetaldehyde and oxygen reactive species (García-Quiroz et al., 2017;Rumgay et al., 2021).Acetaldehyde, which is metabolized from ethanol in alcoholic beverages, damages DNA (Klein et al., 2020).Alcohol has been implicated in raising female hormone levels, thus increasing the risk for hormonerelated cancers (Gill, 2000).However, the effect of alcohol does not appear to directly increase biosynthesis of the major female hormone estradiol; rather, due to the enzymatic degradation of alcohol, estradiol's breakdown to estrone is reduced, allowing estradiol levels to rise.
Ironically, ethanol is also used therapeutically to dehydrate, rupture, and kill cancer cells in human patients through percutaneous injections into the liver (Swierz et al., 2020), implying that alcohol's carcinogenic action may be indirect and mediated by other factors.Additionally, alcohol's harmful effects can cause kidney injury (Varga et al., 2017), and dehydration from alcohol burdens the kidneys' ability to filter blood and maintain fluid and electrolyte balance (Epstein, 1997)

| ALCOHOL AND RHABDOMYOLYSIS
In rhabdomyolysis, skeletal muscle ruptures and intracellular phosphate compounds break apart, releasing excessive amounts of Pi into the serum that cause hyperphosphatemia (Zhang, 2012).Other intracellular components released from damaged muscle cells include myoglobin and creatine phosphokinase, which can disturb the balance of serum electrolytes like calcium and phosphate.Relatedly, between 30% and 40% of rhabdomyolysis cases develop acute kidney injury (AKI) (Cabral et al., 2020), potentially associated with excessive serum Pi levels.Rhabdomyolysis is most often caused by exposure to drugs and toxins (Zhang, 2012), and alcohol is a non-exertional, nontraumatic etiological factor in rhabdomyolysis (Cabral et al., 2020).
Additionally, rhabdomyolysis is associated with polymyositis, an inflammatory condition of muscle that has been linked to an increased incidence of breast cancer (Croce et al., 2011), which may be related to phosphate toxicity that causes inflammatory damage to muscle cells (Czaya et al., 2022).
A large number of cancer cell deaths that occur during cancer treatment can cause tumor lysis syndrome, in which tumor cells release their intracellular contents into the blood, raise levels of serum Pi and other electrolytes, and increase kidney injury and failure (Gupta & Moore, 2018).A review of rhabdomyolysis for clinical practice in AKI noted pathophysiologic similarities with tumor lysis syndrome (Chavez et al., 2016).Of relevance, the incidence of secondary sarcomas was higher in patients treated with radiation, surgery, and chemotherapy than with surgery alone, which could be related to dysregulated levels of phosphate released during tumor lysis from radiation and chemotherapy (Hird et al., 2020).A lowphosphate diet in patients receiving radiation and chemotherapy might help mitigate the risk of phosphate toxicity from tumor lysis syndrome, but more studies are needed in this area.
Alcohol-induced rhabdomyolysis is also associated with inhibition of calcium transport in the sarcoplasmic reticulum of cardiac muscle (Bansal & Bansal, 2017), possibly related to inhibition of ATP hydrolysis due to rising concentrations of the Pi end product (Jarman et al., 2021).Cardiac disturbance in "Holiday Heart," paroxysmal atrial fibrillation, is also more frequent when people increase alcohol consumption during the annual holiday season, even with moderate drinking (Larsson et al., 2014).Importantly, less severe rhabdomyolysis raises serum creatine kinase but is asymptomatic (Khan, 2009), inferring that the association of breast cancer risk with light to moderate drinking may be linked to lower levels of rhabdomyolysis severity.
More studies are needed to investigate the associations of rhabdomyolysis severity with different levels of alcohol exposure.
Relatedly, exposure to alcohol in the human body occurs not only through oral consumption but also through inhalation and dermal contact.Prajapati et al. reported that acute exposure to ethanol disinfectants is non-toxic; "however, blood ethanol levels are affected with long-term exposures to ethanol-based hand sanitizers," which is more likely to have been an issue during the COVID-19 pandemic (Prajapati et al., 2022).Ethanol from hand sanitizers can also enter the body through inhalation of ethanol vapor (MacLean et al., 2017).Health Canada issued warnings that acetaldehyde from ethanol-based hand sanitizers raises concerns about potential carcinogenicity, especially with long durations of use (Canada.ca, 2022).
In addition to rhabdomyolysis, other mechanisms related to alcohol exposure may contribute to carcinogenesis.Aqueous-organic solvents containing alcohol significantly increase the solubility of hydrophobic compounds in toxic waste (Nyssen et al., 1987), implying increased exposure to hazardous and possibly carcinogenic environmental pollutants when coming into contact with these alcohol compounds.
In summary, alcohol contributes to renal burden, which may increase dysregulated phosphate.Alcohol also causes nontraumatic rhabdomyolysis, which increases serum Pi and potentially leads to hyperphosphatemia and phosphate toxicity.Furthermore, rhabdomyolysis is indirectly linked with breast cancer in polymyositis and produces pathophysiologic effects similar to tumor lysis syndrome, which may occur in milder forms with recurrent low exposure to alcohol.

| BREAST CANCER BIOLOGY, PHOSPHATE TOXICITY, AND TUMORIGENESIS
The anatomy of the female breast consists of glandular, fibrous, and fatty tissue attached to the anterior thoracic wall by Cooper's ligaments (Khan & Sajjad, 2022).The breast's specific function is to produce and secrete milk for lactation during breastfeeding, and the breasts also play a role in female sexuality.Milk is produced in the epithelial tissue of the breast, which forms lobules, and the milk flows through ducts connected to the nipple.The breast is also supplied with blood vessels, nerves, and lymphatics.Specific cell differentiation in breast cancer determines the tumor type (Rakha et al., 2022).Table 1  Additionally, inherited breast cancer is linked to mutations in the BRCA1 and BRCA2 genes, which affect about 3% (7500) of annual US breast cancer cases (Centers for Disease Control and Prevention [CDC], 2020).
Cancer in adults is associated with hyperphosphatemia (Papaloucas et al., 2014;Wulaningsih et al., 2013), except for reproductive cancers in females, possibly due to a shift of serum phosphate into reproductive tissue under the mitogenic effect (cell proliferation) of estrogen.Of relevance, phosphate toxicity can occur in cells even if serum Pi levels are normal (Osuka & Razzaque, 2012), and further studies should examine phosphate shift in reproductive cancers.
In support of higher phosphate needs for female reproduction functions, a study of lactating women found elevated mean serum phosphate levels and lower PTH levels compared with controls (Kovacs & Chik, 1995).Additionally, intestinal phosphate absorption doubles in pregnancy as serum calcitriol levels rise (Kovacs, 2021).
Furthermore, breast milk contains phosphorus, and researchers using P-31 MRS suggested that higher levels of the phosphate metabolite phosphomonoester found in the lactating breast were related to the higher proportion of milk-producing epithelial tissue in the breast lobules (Twelves et al., 1994).Increased phosphate demand during pregnancy and lactation might lower the breast cancer risk associated with dysregulated Pi, and only 3% of women develop breast cancer while breastfeeding (Hermann & Nolson, 2012).Breast cancer risk also drops by 4.3% for every 12 months of breastfeeding (Stordal, 2023).
Excessive cell growth during tumor promotion and progression is stimulated by the uptake of excess Pi into ribosomal RNA in cells (Ward & Griffin, 1955).Epithelial tissue, such as lacteal duct tissue in the breast, has storage properties suitable for phosphate sequestration and the growth of carcinomas, such as invasive ductal carcinoma, which accounts for approximately 80% of breast cancers (Bolhasani et al., 2020).Compared with normal tissue, breast carcinomas had a higher and faster uptake of the phosphorus isotope P32 with longer retention (Jones et al., 1940), and mean Pi levels in breast cancer tissue were more than three-fold higher than normal tissue (Sivakumar & Mohankumar, 2012).
Earlier studies of breast cancer using P-31 magnetic resonance spectroscopy (MRS) found lower levels of Pi, adenosine triphosphate (ATP), and other phosphate metabolites in normal breast tissue compared with breast tumors (Kalra et al., 1993;Ng et al., 1989;Park & Park, 2001;Redmond et al., 1991;Sijens et al., 1988).Furthermore, the sodium phosphate cotransporter NaPi-IIb (SLC34A2) is highly expressed in breast cancer (Chen et al., 2010;Russo-Abrahão et al., 2018).However, H + -dependent phosphate transporters in breast cancer cells were recently found to increase Pi uptake by fivefold compared with sodium phosphate cotransporters, which researchers suggested occurs when sodium phosphate cotransporters become saturated with increasing concentrations of Pi in the tumor microenvironment (Lacerda-Abreu et al., 2019).
Cell signaling in tumorigenesis is also activated by high levels of Pi (Liu et al., 2009), and tumor neovascularization is stimulated as well (Lin et al., 2015).Additionally, high Pi levels are associated with chromosome instability (Chudek et al., 2007), and Pi levels measured in extracellular tissue are associated with metastatic cancer progression (Bobko et al., 2017).Schipper et al. (1996) proposed that dysregulated metabolic pathways linked to cancer promotion may be reversible, implying that dietary phosphate modification may reduce cancer risk.
A review of the research literature suggests a strong association between the risk of cancer incidence and dietary patterns that are high in phosphorus (Brown, 2020b).
Figure 2 shows the cell signaling pathway used by high dietary phosphate to stimulate cancer cell growth.Note that kinases are enzymes that add phosphate groups to substrates, and phosphatases are enzymes that remove phosphate from substrates.High dietary phosphate activates a signaling pathway in which PI3K phosphorylates Akt (protein kinase B) (Liu et al., 2009).Akt activates mTOR kinase, which suppresses cell apoptosis and up-regulates protein synthesis and cell proliferation (Guertin & Sabatini, 2007).High dietary phosphate was found to activate Akt phosphorylation, facilitating capdependent protein translation that increased lung tumorigenesis in mice (Jin et al., 2009).Furthermore, high dietary phosphate inactivated both phosphatase and tensin homolog (PTEN), a tumor suppressor, and carboxy-terminal modulator protein (CTMP), a negative regulator of Akt activity.

| ONCO-NEPHROLOGY AND DYSREGULATED PHOSPHATE
This section provides additional evidence supporting the association of phosphate toxicity with breast cancer.Dysregulation of phosphate metabolism is associated with kidney pathology (Brown, 2020c;Brown & Razzaque, 2015), and kidney pathology is among the risk factors associated with breast cancer (Malyszko et al., 2020).
Thus, breast cancer and kidney disease potentially share dysregulated F I G U R E 2 Phosphate and cancer cell signaling (Brown & Razzaque, 2018).High dietary phosphate stimulates the phosphoinositide 3-kinase (PI3K)/Akt/mTOR signaling pathway and inactivates tumor suppression, increasing tumorigenesis.phosphate metabolism as a common pathophysiological determinant.Chronic kidney disease (CKD) is so strongly associated with cancer that a transdisciplinary medical specialty evolved to study a link between nephrology and oncology, onco-nephrology (Lacava et al., 2015;Rosner et al., 2021).The prevalence of CKD at the time of cancer diagnosis was reported as 12% to 53%, and glomerular filtration was reduced in 50%-60% of cancer patients (GFR < 90 mL/min/1.73m 2 ) (Cosmai et al., 2020), leading to recommendations for a comprehensive onco-nephrological examination in cancer patients to evaluate disturbances in electrolytes, including phosphate.
Kidney vulnerability to nephrotoxic injury is increased by exposure to exogenous toxins and drugs (Perazella, 2009).Dysregulated metabolism and electrolyte disorders also increase patient vulnerability to renal toxicity, and a significant number of patients are also vulnerable to CKD caused by phosphate nephropathy.Note that hypophosphatemia also commonly occurs in cancer patients as a serious complication.Hypophosphatemia is associated with various conditions such as malnutrition from inadequate dietary phosphate intake, adverse therapy effects of chemotherapy drugs, critical illness with poor intestinal phosphate absorption, or a large transcellular Pi shift, including rapid Pi absorption by growing malignancies in tumor genesis syndrome (Adhikari et al., 2021).
Researchers in onco-nephrology are studying kidney disease and electrolyte/acid-base disturbances as complications in cancer biology and as effects of treatments for cancer (Capasso et al., 2019).CKD and AKI are highly prevalent in cancer patients and can be severe.for >3 months (Levey et al., 2002).Advanced stages of CKD, stages 3-5, in women diagnosed with breast cancer are associated with an increased risk of mortality, regardless of whether the women received chemotherapy or radiotherapy (Hill et al., 2020).
Among women with breast cancer, an eGFR < 60 mL/ min/1.73m 2 , compared with no eGFR reductions, was associated with a 2-to 2.5-fold increased risk of breast cancer mortality in a model adjusted for most known risk factors of cancer death (Iff et al., 2014).The researchers implied that the increased cancer mortality risk associated with a lower eGFR could be related to exposure to higher serum levels of uremic toxins, but the precise biological mechanism was not clear and was likely multifactorial.By contrast, a meta-analysis that lacked "sufficient power" found no significant association between reduced renal function in CKD patients and the overall risk of cancer (Wong et al., 2016).However, relative to patients in the meta-analysis with higher eGFR, dialysis patients had an increase in cancer deaths and an increased incidence of endocrine, urinary tract, and digestive tract cancers.
Although excess phosphate in breast tissue may not directly attract other toxins into the breast, excessive accumulation of Pi, considered a uremic toxin by some researchers, is associated with more than 153 other uremic toxins originating from impaired renal function (Falconi et al., 2021).Uremic patients were found to have persistently high serum levels of carcinogenic compounds, which is associated with an increased incidence of cancer in patients with chronic renal failure (Hu et al., 2022).Women with CKD have an increased risk of mortality from breast cancer related to the release of proinflammatory cytokines (Hill et al., 2020), which is stimulated by uremic toxins, primarily indoxyl sulfate, p-cresyl sulfate, and indole-3-acetic acid (Brito et al., 2020).
Other conditions associated with dysregulated phosphate metabolism include ectopic calcification, hyperparathyroidism, and low levels of vitamin D-and each condition is associated with breast cancer, thereby indirectly linking breast cancer with phosphate toxicity.
For example, microcalcification clusters in mammograms were an independent risk factor associated with breast cancer in a cohort of Swedish women (Azam et al., 2021).Primary hyperparathyroidism shares characteristics in common with breast cancer, suggesting "common etiological pathways" (Arrangoiz et al., 2019).Up to 30% to 40% of patients diagnosed with non-aggressive breast cancer have an occurrence of hypercalcemia, potentially caused by primary hyperparathyroidism from parathyroid gland hyperplasia or an adenoma.
Even 15 years after parathyroidectomy, the risk of malignancy persists, "suggesting genetic predisposition or environmental factors as causal mechanisms rather than biochemical changes" (Sigvaldason et al., 2016).Many studies have also found an inverse association between the risk of breast cancer and serum levels of 25(OH)D3 (Atoum & Alzoughool, 2017), and calcitriol is inversely associated with cancer cell growth (Trump, 2018).
F I G U R E 3 The link between alcohol and increased breast cancer risk is mediated by alcohol-induced renal burden and nontraumatic rhabdomyolysis, leading to hyperphosphatemia and phosphate toxicity associated with tumorigenesis.
, which can contribute to dysregulated serum Pi.Because serum concentrations of calcitriol and 25(OH)D3 are reduced in people with alcoholism, researchers hypothesized that alcohol could interfere with the biosynthesis of calcitriol in breast tumor cells, which is enzymatically increased by 25(OH)D-1αhydroxylase expressed by gene CYP27B1 and decreased by 1,25-dihydroxyvitaminD-24 hydroxylase, expressed by CYP24A1 (García-Quiroz et al., 2017).Moderate chronic ethanol intake in a murine model was found to increase tumor cell CYP24A1 and decrease renal CYP27B1, suggesting reduced renal biosynthesis of calcitriol from 25(OH)D3 and degradation of both 25(OH)D3 and calcitriol in breast cancer cells.In support of potential mediation by phosphate toxicity in alcohol-related breast cancer, hyperphosphatemia-induced release of FGF23 and its cofactor α-klotho (Buchanan et al., 2020) suppress CYP27B1 and induce CYP24A1 expression to "inhibit the synthesis and promote the catabolism" of calcitriol (Jacquillet & Unwin, 2019).

F
I G U R E 1 Endocrine regulation of inorganic phosphate (Pi)(Brown, 2020c).(A) Pi absorption in the intestines is increased by bioactive vitamin D3 released by the kidneys, which increases serum Pi. (B) Fibroblast growth factor 23 (FGF23) from bone and parathyroid hormone (PTH) from the parathyroid glands inhibit kidney reabsorption of Pi and increase phosphaturia.(C) PTH also increases the resorption of calcium from bones.Additionally, α-klotho, a cofactor with FGF23, is released from the kidneys and the brain.

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Cancer-related metabolic disturbances" and "tissue deposition of paraproteins" in cancer are associated with the risk of AKI.Patients with glomerulopathy have a higher risk of cancer than the general population, and cancer mortality is highest in patients requiring dialysis for AKI.Patient survival is also very poor in cancer-associated hypercalcemia, which is often caused by the release of PTH.An excessive risk of cancer has been identified in patients with early stages of CKD, defined by the National Kidney Foundation Kidney Disease Outcome Quality Initiative as either kidney damage or an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m 2

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| GT: ALCOHOL AND BREAST CANCER MEDIATION BY PHOSPHATE TOXICITYBased on the analysis of evidence from published research findings, the GT in the present theoretical paper proposes that the association of alcohol consumption with the risk of breast cancer is mediated by phosphate toxicity.A hypothetical causative pathway is illustrated in the directed acyclic graph in Figure3.Alcohol consumed in a dose-dependent manner in women, even at low levels, can induce renal burden, which compromises Pi regulation.Alcohol also causes nontraumatic rhabdomyolysis, which ruptures skeletal cell membranes, releasing excessive intracellular phosphate into the blood serum, increasing hyperphosphatemia and the risk of phosphate toxicity.Tumorigenesis is also associated with phosphate toxicity.Thus, phosphate toxicity mediates the association between alcohol consumption and increased breast cancer incidence.9| CONCLUSIONSStudies are lacking in the research literature that have examined a link between phosphate toxicity, breast cancer, and alcohol consumption.The present theoretical paper used a GT literature-review method to analyze published research findings and propose that the association of alcohol consumption with increased breast cancer incidence is mediated by alcohol-induced renal burden and nontraumatic rhabdomyolysis, leading to hyperphosphatemia and phosphate toxicity.Phosphate toxicity is also associated with increased cell signaling in tumorigenesis, and phosphate toxicity is potentially a common factor linking cancer and kidney disease in onco-nephrology.Novel insights in this paper may lead to future research and interventions that raise public awareness of breast cancer risk and alcohol consumption, mediated by phosphate toxicity.
lists the most common tumor types.
Metastatic breast cancerStage 4 cancer spreads to other organs: lungs, bones, liver, and brain.