Encyclopedia
Please note this is a comparison between Version 1 by Ronald B. Brown and Version 2 by Rita Xu.
Breast cancer is associated with phosphate toxicity, the toxic effect from dysregulated phosphate metabolism that can stimulate tumorigenesis. Phosphate toxicity and dysregulated phosphate metabolism are also associated with bone mineral abnormalities, including excessive bone mineral loss and deposition.
- breast cancer
- bone mineral density
- phosphate toxicity
1. Introduction
An association of breast cancer with high bone mineral density (BMD) has been reported in the literature [1], but the underlying causative mechanisms of this relationship have not been established. For example, a 2013 meta-analysis of ten prospective studies involving 70,878 postmenopausal women found that high BMD was associated with increased breast cancer risk [2]. Also in 2013, a retrospective study of Israeli women found an association between breast cancer and higher BMD in the lumbar spine, femoral neck, and total hip [3]. A more recent case–control study in 2019 confirmed that breast cancer in Brazilian women was associated with high BMD in the lumbar spine, but not in the femoral neck or total femur [4]. Interestingly, a 2022 case–control study reported that BMD in women with breast cancer was higher compared with those in a control group, even though the breast cancer cases had lower average vitamin D levels, which are normally associated with bone health [1].
Further contributing to the research literature on bone mineral density and breast cancer is the opposite finding of increased osteoporosis risk associated with breast cancer in postmenopausal women, suggesting that breast cancer may share common “biochemical links” with low bone mineral density [5]. However, treatment for breast cancer is also associated with bone loss [6], and treatment effects must be considered in assessing osteoporosis risk associated with breast cancer in women. On the other hand, hormone replacement therapy (HRT) increases BMD, and HRT is also associated with increased risk of breast cancer [7]. These findings suggest that both high and low BMD may be biochemically linked to breast cancer through unknown factors.
Adding to the controversy, other studies have failed to find an association between breast cancer and BMD [8][9][10][11][8,9,10,11]. Part of this inconsistency in study findings may be explained by the differing intervals of repeated follow-up measures to detect longitudinal changes in bone mineral density related to the incidence of breast cancer [9]. Importantly, healthy bone mineral density levels are neither excessively high nor low, and elevated bone mass has been associated with degenerative bone disease, such as osteoarthritis [12][13][12,13]. Furthermore, phosphate toxicity, the pathogenic effect of dysregulated phosphate metabolism in the tissues of the body, is associated with tumorigenesis [14] and negatively impacts bone health [15]. Yet, no studies have investigated phosphate toxicity and dysregulated phosphate metabolism as factors associated with high and low levels of bone mineral density in breast cancer. A brief description of phosphate metabolism and phosphate toxicity follows.
The metabolism of serum inorganic phosphate (Pi) is regulated through endocrine hormones secreted by the bone–kidney–intestine–parathyroid axis [16]. Intestinal absorption of Pi is increased as the kidneys release the bioactive form of vitamin D, 1,25(OH)2D3, also known as calcitriol. The kidneys reabsorb Pi to maintain normal serum Pi levels and excrete excess Pi in the urine. Fibroblast growth factor 23 (FGF23), released from bones, and parathyroid hormone (PTH) released from the parathyroid glands, help to regulate Pi levels by inhibiting kidney reabsorption of excessive Pi and increasing urinary phosphate excretion.
Phosphate toxicity from excessive accumulation of phosphate in the tissues of the body can accelerate aging, cause bone deformities, and reduce longevity [17]. Importantly, hyperphosphatemia (excessive amounts of Pi in the serum) can lower the serum calcium levels, triggering PTH to resorb bone and release calcium into the serum to restore normal levels of calcium. Dysregulated amounts of serum Pi also increase calcium phosphate levels, increasing ectopic calcification throughout the body, including calcium phosphate deposits of hydroxyapatite in soft tissues and bone [16]. Moreover, high calcium-phosphate product is associated with C-reactive protein [18], and C-reactive protein is associated with bone mineral loss [19].
2. Phosphate Toxicity and Tumorigenesis
Elevated levels of Pi within the tumor microenvironment stimulate cell signaling in tumorigenesis [20][28] and stimulate tumor neovascularization in lung and breast cancer cells [21][29]. Excess phosphate uptake into the nuclear RNA of cells was shown to stimulate tumor growth, which was delayed when phosphorus uptake was suppressed [22][30]. Sodium phosphate cotransporters that sequester extracellular Pi are overexpressed in cancer cells of the ovaries, lungs, breasts, and thyroid gland [23][24][31,32]. The rate of transport of high Pi concentrations into breast cancer cells through H+-dependent Pi transporters is five times that of sodium phosphate cotransporters [25][33]. Additionally, a letter published in Science as far back as 1946 noted the detection of breast tumors through increased uptake of the radioactive isotope phosphorus-32, compared with lower uptake of the phosphorus isotope by normal breast tissue [26][34]. A comparison of mouse models also showed that the effects of cachexia in cancer were similar to the effects of phosphate toxicity, with sarcopenia (muscle-wasting), osteoporosis, spinal kyphosis, and organ atrophy [27][35].
Hyperphosphatemia in patients was associated with chromosome instability and increased proliferation of parathyroid cells [28][36], and elevated levels of Pi in extracellular tissue were associated with cancer metastasis in a mouse model of breast cancer [29][37]. High dietary intake of phosphate in the Health Professionals Follow-Up Study was associated with high-grade prostate cancer [30][38], and another study found that serum phosphate levels were abnormally higher in cancer patients compared with control patients [31][39]. Experimental animals fed high-phosphorus diets developed lung tumors [32][40] and skin cancer [33][41]. Furthermore, tumor cells of the lung and colon in humans contain up to twice the amount of Pi as normal cells [34][42].
3. Bone Remodeling and Dysregulated Phosphate Metabolism
Normal bone metabolism renews bone tissue through a balance of mechanisms that break down and remove worn bone tissue, and replace the discarded tissue with deposits of new bone:
“Bone remodeling is the process by which bone is renewed to maintain bone strength and mineral homeostasis. Remodeling involves continuous removal of discrete packets of old bone, replacement of these packets with newly synthesized proteinaceous matrix, and subsequent mineralization of the matrix to form new bone. The remodeling process resorbs old bone and forms new bone to prevent accumulation of bone microdamage”.
If bone remodeling mechanisms that normally build up and break down bone become unbalanced, metabolic bone disorders may occur, such as osteoporosis, in which “bone resorption outpaces bone formation” [36][44]. Of relevance, mineral and bone disorder is associated with chronic kidney disease (CKD-MBD), in which serum Pi homeostasis is often dysregulated [37][38][45,46]. Additionally, “studies have shown that patients with chronic renal failure (CRF) are more likely to suffer from breast cancer and other malignant tumors” [39][47]. Furthermore, dysregulated phosphate and phosphate toxicity potentially mediate an association of mineral bone disorder with breast cancer by causing excessive release of PTH in hyperparathyroidism (known as secondary hyperparathyroidism).
“PTH can produce catabolic or anabolic effect(s) on bone metabolism depending on the level of the hormone, periodicity, and duration of exposure”.
Loss of healthy bone in cancer is found in combination with increases in abnormal bone deposits, or osteoblastic skeletal lesions [41][42][49,50]. Abnormal calcification of bone is seen in metastasis of the breast, prostate, and other cancers [43][51]. Bone deposits are also associated with osteosclerosis, a hardening in which excess minerals are abnormally deposited into the bone matrix [44][52]. The main causes of osteosclerosis include secondary hyperparathyroidism [45][53], which is commonly associated with hyperphosphatemia in renal insufficiency [46][54]. “It has already been established that in end-stage renal disease, hyperphosphatemia causes soft tissue calcification,” and dysregulated phosphate metabolism may be responsible for the observed associations of calcification in normal populations [47][55]. Additionally, ectopic calcification from calcium phosphate deposits in the form of microcalcifications of the breast has been associated with increased risk of breast cancer [48][56].
Low vitamin D levels associated with dysregulated phosphate metabolism are common in CKD [49][57], and breast cancer risk is inversely associated with levels of vitamin D [50][58]. Breast cancer metastasis is also autonomously promoted by vitamin D deficiency [51][59]. Furthermore, evidence suggests that increased breast cancer risk is associated with high levels of FGF23 [52][60] and PTH [53][61], which are also associated with dysregulated phosphate metabolism.
4. Metastatic Breast Cancer
Metastatic breast cancer, stage IV breast cancer that has spread to other organs, is the most advanced form of breast cancer affecting approximately 30% of women with the disease, and is “generally incurable” [54][62]. Bone is the most common site of metastases in metastatic breast cancer [55][63]. Importantly, both abnormal bone deposition and bone loss (osteolytic skeletal lesions) appear early in metastatic breast cancer, but breast cancer metastases mostly cause bone loss:
“Metastases leading to overall bone loss are classified as osteolytic. Those leading to excess bone deposition are considered osteoblastic. However, both bone degradation and deposition likely occur early in the metastatic process. The majority of breast cancer metastases ultimately cause bone loss”.
Although breast cancer bone metastases are predominantly osteolytic, 15–20% of breast cancer bone metastases cases “have a predominant osteoblastic component” [56][64]. Excessive bone deposition in early osteoblastic metastases may account for the increased risk of breast cancer associated with higher BMD. Furthermore, Ramirez and Fielder noted that a “high local phosphate concentration during osteolysis” is observed in breast cancer and bone metastases, which requires further investigation [57][65]. These findings provide plausible mechanisms by which dysregulated phosphate metabolism and phosphate toxicity are associated with BMD changes in breast cancer.
