Abstract
Breast microcalcification is a potential diagnostic indicator for non-palpable breast cancers. Microcalcification type I (calcium oxalate) is restricted to benign tissue, whereas type II (calcium hydroxyapatite) occurs both in benign as well as in malignant lesions. Microcalcification is a pathological complication of the mammary gland. Over the past few decades, much attention has been paid to exploit this property, which forms the basis for advances in diagnostic procedures and imaging techniques. The mechanism of its formation is still poorly understood. Hence, in this paper, we have attempted to address the molecular mechanism of microcalcification in breast cancer. The central theme of this communication is “how a subpopulation of heterogeneous breast tumor cells attains an osteoblast-like phenotype, and what activities drive the process of pathophysiological microcalcification, especially at the invasive or infiltrating front of breast tumors”. The role of bone morphogenetic proteins (BMPs) and tumor associated macrophages (TAMs) along with epithelial to mesenchymal transition (EMT) in manipulating this pathological process has been highlighted. Therefore, this review offers a novel insight into the mechanism underlying the development of microcalcification in breast carcinomas.
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Introduction
Breast cancer ranks second among different types of cancers worldwide, and is still one of the major leading causes of morbidity and mortality among women. The mortality rate could be reduced markedly if the breast cancers were diagnosed and treated at early stages. Mammography is widely used for early screening and detection of breast cancers [1] via the utilization of X-rays (at low dose) to visualize breast tissues clearly, and to screen various subtle abnormalities including pathological lesions. Use of mammography provides a benefit to women by reducing the mortality by as much as 30 % [2, 3]. Mammography detects both palpable and non-palpable breast lesions, based on abnormalities like the appearance of microcalcification [4–6].
Bright white flecks that appear on mammograms are a signature of calcification. They are broadly categorised as ‘macro’ and ‘micro’ calcification [7–13]. Macrocalcifications are coarse, large white dots or specks in nature (>0.5 mm in diameter) [11] that are often randomly dispersed throughout the breast tissue, and are most often found in non-cancerous tissues [13–15]. Microcalcification clusters are tiny specks (<0.5 mm in diameter) of calcium deposits [10, 11] appearing on the mammographic image [16, 17]. Accumulating evidence shows a positive association between microcalcification and malignancy, along with the grade of the breast cancer [18–20]. Moreover, literature reports suggest that the presence of microcalcification in breast tissue can be a diagnostic marker for breast cancer [4, 21, 22]. Microcalcification also correlates with increased cancer progression and metastasis of breast cancer [18–20, 23]. Thus, there is an urgent need to understand the underlying molecular mechanism of this pathophysiological mineralization.
In this review article, we investigate a subpopulation of heterogeneous breast tumor cells that acquires osteoblastic properties. These osteoblast-like cells drive the process of pathological calcification in breast cancer tissues [24–28]. Based on literature reports, we have outlined herein how potent osteoinducers of bone (morphogenetic proteins; BMPs), and tumor associated macrophages (TAMs) play a crucial role in enhancing the pathological mineralization.
Classification of Microcalcifications
Based on their morphological appearance, microcalcifications have been classified into the following five categories: i) “Ring shaped” in 100 % of benign lesions; ii) “Round microcalcification” in 22 % of malignant lesions; iii) “Pulverulent” (too fine) in 40 % of malignant lesions; iv) “Punctate” in 66 % of malignant lesions, and v) “Vermicular” in 100 % malignant lesions [29]. Breast Imaging Reporting and Data System (BI-RADS) classifies tumors based on morphology descriptors, mammographic density, presence of calcification, and their distribution on mammograms (calcification presents in BI-RADS I and BI-RADS II) [30]. Every morphology descriptor assigns a category to a lesion which helps in determining its malignant potential as: 1) benign, 2) intermediate, or 3) malignant [30]. Based on mammographic appearances, primary calcifications have also been classified as a: 1) powdery form, 2) crushed stone-like, or 3) casting-type [21].
On the basis of chemical composition and physical properties, microcalcifications are also categorized into two types, as type I (calcium oxalate) and type II [calcium hydroxyapatite (HA)] [31]. Light microscopic views show that calcium oxalate crystals are amber in color and are partially transparent, while HA crystals are grey/white in color and are opaque [31]. Under polarized light, type I is birefringent, whereas type II is non-birefringent [31]. Deposition of calcium in the form of calcium oxalate occurs mostly in benign ducts, whereas the HA form often occurs both in benign and in proliferative lesions of breast carcinoma [31–34]. Further, some studies provide evidence that type II HA crystals are often found in the invasive infiltrating cells of breast cancer [18–20]. Moreover, compact clusters (20 microcalcification/cm2) represent a malignant condition [35, 36]. It is not yet understood whether the microcalcification functionally modulates the pathophysiology of this disease, or if this is just a consequence of disease development.
It is important to note here that microcalcification has been found in different body organs/tissues such as iliac artery, medial artery, thyroid nodules, testis, ovary, brain and kidney in association with various pathophysiologies depending on the tissue/organ it is found in. Beside mammography, these microcalcifications can be detected by other techniques such as ultrasonography, H&E staining, Von Kossa staining, etc. as summarized in supplementary Table S1.
HA Microcalcification and Malignancy of Breast Cancer
HA microcalcification contains a lower amount of carbonate in malignant lesions when compared to benign tissues [18, 19]. A possible explanation for the association of HA with malignant lesions was given by Morgan et al., where they found that HA has the potential to induce mitogenesis in MCF-7 and Hs578T breast cancer cells [20]. Moreover, treatment of breast cancer cells with HA enhanced matrix metalloproteinase (MMP) activity, and stimulated prostaglandin production to intensify its effect [20]. As a mechanism, it was demonstrated that the elevation of prostaglandin levels by HA treatment was due to upregulation of cyclooxygenase-2 (Cox-2), and that HA crystals can induce MMP activity by upregulating the inflammatory cytokine interleukin-1β (IL-1β) [37]. A recent study by Cox et al., documented that an invasive sub-clone of breast cancer Hs578T cells shows more competency to have (HA containing) mineralization when compared to parental Hs578T cells and normal breast epithelial MCF10A cells. Lung metastasizing breast cancer (4 T1 cells) also exhibited formation of mineralization sooner than that of the invasive sub-clone of Hs578T cells [102]. These data suggest that microcalcification can be a strong predictor for malignancy of breast cancers, and these studies also help to understand the role of HA in malignant tissues.
Role of Matrix Vesicles in Microcalcification
The mechanism for the deposition of calcium crystals in the form of microcalcification is poorly understood. To discover this mechanism, much attention has been paid to the role of matrix vesicles (MVs). MVs are small (20–200 nm) membrane enclosed structures, where various mechanisms for their biogenesis have been proposed. The most widely accepted mechanism is that MVs are derived by the process of budding off or being pinched out from selected sites of the plasma membrane of calcifying competent cells like osteoblasts [38, 39], odontoblasts [40–42], chondrocytes [43, 44], or embryonic stem cells [45] during the period of mineralization. We have listed all types of known calcifying cells which produce MVs in Table 1 [38–57]. Many studies show that breast tumor cells also produce MVs [50, 52, 53, 56]. The lipid membrane composition of these synthesized MVs differs significantly from the parent plasma membrane. The membranes of MVs are enriched in tissue non-specific alkaline phosphatase (TNAP) [58], phosphatidylserine (PS) [59], annexins [60], NaPi transporter [61], nucleotide pyrophosphatase phosphodiesterase 1(NPP1; PC1), and phospho1 (PE/PC phosphatase) [62], all of which facilitate the formation of HA crystals by supplying calcium and phosphate ions to MVs.
An important step in mineralization is the formation of the first crystal of HA (i.e., starting material for calcification) which is synthesized inside MVs by calcifying cells [63]. These MVs act as vehicles for the transfer of newly synthesized monocrystal from inside to the outside of the cell, and form a nucleational core of HA in the extracellular fluid [64]. The phenomenon of propagation of this monocrystal to appear as mature crystallized calcium is largely unexplored. However, it is thought that when HA crystals are exposed to the extracellular matrix, they serve as a template for the synthesis of the mature crystal [65].
MVs are involved both in normal as well as in ectopic calcification. Using transmission electron microscopy, it was found that MVs in mouse atheroma and human fibrous caps that were associated with solid microcalcification [66]. It was suggested that sortilin 1 (a type I transmembrane protein which belongs to the family of vacuolar protein sorting 10) induces MVs to progress in this process [67]. Moreover, recent findings by New et al., report that in atherosclerotic plaques, macrophages release MVs, and these MVs drive the formation of microcalcification [68]. All these findings suggest that MVs play a pivotal role in pathophysiological mineralization of different organs/tissues.
Basic Mechanism for Microcalcification in Breast Cancer Tissues
As we have discussed above, breast tumor cells produce MVs. What has not yet been reported is whether the composition of the lipid membrane of MVs from breast tumors matches those MVs which are derived from calcifying cells. Recent findings document that secreted MVs from osteosarcoma cancer cells contained similar kinds of components as those from osteoblast cells [69]. The composition of MVs of breast cancer cells has not yet been investigated. However, breast cancer tissues/cells showed increased levels of MV components (which are known to be involved in the calcification process) as compared to control tissues/normal breast epithelial cells (Table 2) [70–86] For example, many Ca2+ ion channels such as the transient receptor potential (TRP) cation channels and associated proteins annexin A2, A4, and A5, were found to be increased in breast cancer cells. These proteins can increase the concentration of Ca2+ ions inside MVs/cells [76, 87]. Other evidence shows that expression of the transient receptor potential cation channel 7 (TRPM7) is increased in breast cancer cells, and promotes cell proliferation, migration, and metastasis [112, 113, 116, 120, 121]. Similarly, other studies indicate that breast tumor cells accumulate more phosphate ions inside cells by increasing the expression of NaPi-IIb (SLC34A2) cotransporter as compared to noncancerous cells [79]. Moreover, calcification of breast cancer 4 T1 cells was aborted when cells were treated with phosphonophormic acid, an inhibitor of type-II Na-Pi cotransporter [71].
Collectively, these findings suggest that microcalcification in breast tumors, similar to other organs/tissues, may proceed through a similar process i.e., mediated through MVs. Moreover, metastatic cancer cells/tissues showed increased levels of several components of MVs (such as TRP channel, annexins, ALP etc.,) compared to non-metastatic cancer cells/tissues (Table 2). It is currently reported that expression of two Ca2+ channels (i.e. TRPM7 and TRPC1) are increased in infiltrating ductal carcinoma with microcalcification [83]. This evidence supports the idea that the metastatic/invasive breast cancer cells might have more competency for pathological microcalcification as compared to non-metastatic/non-invasive cancer cells.
Switch of Breast Cancer Cells into Osteoblast-Like Cells during Microcalcification
The literature states that at the time of pathological calcification (of different tissues), one cell type needs to transform into osteoblast-like cells, which mimics the process of physiological calcification [88, 89]. For example, vascular smooth muscle cells (VSMCs) transdifferentiate into osteoblast-like cells which process calcification in vascular or arterial walls [88, 89].
Thus, the existence of osteomimetic cells in breast tumors correlates with the occurrence of microcalcification. In fact, the presence of cells with osteoblastic and chondroblastic characteristics in breast tumor isolated from a cancer patient has been reported, and osteoblastic cells derived from this tumor show expression of ALP and OPN, both of which are markers of osteoblastic differentiation [70]. Various experimental studies have revealed that at the time of pathological mineralization, osteomimetic cells express many transcription factors and bone matrix proteins involved in physiological calcification, just the same as that of osteoblasts, (Table 3) [24–28, 90–134]. For instance, the MCF-7 breast cancer cell line showed expression of ALP when cells were treated with different agents such as 17β-estradiol [74]. A study by Cox et al., recently reported that metastatic breast cancer 4 T1 cells expressed a high level of ALP while MCF10A normal breast epithelial cells were unable to express ALP, when both cells were treated with an osteogenic cocktail [71]. They also found that treatment of 4 T1 cells with levamisole, an inhibitor of ALP, inhibited mineralization, a late marker for osteoblast differentiation [71]. Many findings have shown elevated levels of ALP in, i) the serum of breast cancer patients when compared to controls [75], ii) in patients with bone metastases when compared to patients without bone metastases [72, 73], and, iii) advanced stages of breast cancer as compared to early stages and/or healthy controls [135, 136]. These data indicate that in certain circumstances, a subpopulation of epithelial breast cancer cells may switch to osteoblast-like cells.
During bone formation, osteoblastic transcription factors such as Runx2 and Msx2 (which are expressed by osteoblast cells), drive ALP expression, mineralization, and also augment expression of osteoblastic matrix proteins such as osteocalcin (OCN), osteopontin (OPN), osteonectin (OSN) and bone sialoprotein (BSP). These matrix proteins mainly form the bone matrix, and also manipulate the calcification process [110, 137–140]. Accumulating evidence reveals that both breast cancer cells and tumor tissues expressed these osteoblastic transcription factors and matrix proteins [94, 123, 141–144]. For instance, Runx2 activity was found in LCC15-MB and MDA-MB-231 breast cancer cells, but not in normal human mammary epithelial cells (HMECs) [94]. Expression of Msx2 was found to be increased in MCF7, T47-D, SKBR3, and ZR75-1 breast cancer cells [26]. Moreover, increased expression of OPN and OSN have been shown to be associated with breast cancer microcalcification, and OPN expression was upregulated in infiltrating carcinomas with microcalcification [123, 124]. Similarly, infiltrating ductal carcinomas showed an increased expression of BSP [27]. Moreover, the levels of OCN and BSP, similar to ALP, were found to be increased in the serum of breast cancer patients as compared to benign cancer patients [28, 71, 120].
All these evidence suggests that in the pathophysiologic condition, breast cancer cells have a propensity to gain osteoblast characteristics (Fig. 1). Next, we discuss how breast cancer cells acquire the osteoblast-like phenotype.
Basic model of microcalcification formation. a A subpopulation of epithelial breast tumor cells potentially acquires the mesenchymal phenotype through epithelial to mesenchymal transition (EMT). b These mesenchymal cells acquire osteoblast like properties, and secret hydroxyapatite crystals which are deposited at the invasive front of breast tumors
Breast Cancer Cells Acquire Osteoblastic Characteristics during Epithelial to Mesenchymal Transition
It is important to mention here that osteoblasts are generated from the differentiation of mesenchymal cells [145]. A sub-population of heterogeneous epithelial cancer cells of a tumor usually undergoes epithelial to mesenchymal transition (EMT). This subpopulation of cells governs a more invasive potential, and are responsible for metastasis [124]. Invasive MDA-MB-231 breast cancer cells showed an increased expression of the osteoblastic transcription factor Runx2 as compared to non-invasive breast cancer MCF7 cells. MDA-MB-231 cells are more mesenchymal in nature, as compared to MCF7 [96]. Similarly, Runx2 DNA binding activity was also higher in MDA-MB-231 cells as compared to normal HMECs [146]. Hassan et al., recently demonstrated that the microRNA miR-218 increases the metastatic potential of breast cancer cells by enhancing the expression of Runx2 [90]. Moreover, expression of Runx2 in cancer cells positively associates with the EMT phenotype and the metastatic properties of these cells, with a concomitant increase of OCN [143]. Ectopic expression of Runx2 also converts mesenchymal stem cells to osteoblast cells [147]. Thus, expression of Runx2 in breast cancer cells might increase invasive potential, and also transdifferentiate cancer cells to osteoblast-like cells.
Similarly, another osteoblastic transcription factor, Msx2, was found to be frequently dysregulated in cancers [148]. Msx2 is also a potent inducer of the EMT phenotype of cancer cells [149, 150]. The expression of Msx2 was found to be increased in infiltrating breast cancer cells which are more invasive by nature, when compared to non-infiltrating breast cancer cells [150]. Moreover, the level of Msx2 could be an indicator for malignancy as it was elevated gradually from benign to malignant lesions [151]. Overexpression of Msx2 inhibits cell growth [26]. These data indicate that Msx2 might have a significant role in promoting EMT of cancer cells by halting cell growth. Similar to Runx2, expression of Msx2 converts mesenchymal progenitor cells to osteoblast cells [152].
We have discussed above that metastatic breast cancer cells show high osteoblastic gene expression of Runx2, Msx2, OPN, OSN, BSP, and ALP, with increased mineralization [26, 27, 96, 123, 124]. Moreover, it has been reported that the microcalcification surrounding breast tissue correlates with mineralized malignant cells [153]. These findings suggest that during tumorigenesis, a population of epithelial cancer cells of a breast tumor gains the mesenchymal phenotype through EMT, and at least a few of these invasive cancer cells which acquire mesenchymal characteristics may differentiate into “osteoblast-like” cells; presumably driven by osteoblastic factors.
A recent study supports this concept, since the co-existence of mesenchymal markers (vimentin and β-Catenin) and osteoblastic proteins (OPN and BMP-2) was greater in infiltrating carcinomas with microcalcification when compared to infiltrating ductal carcinomas without microcalcifications [124]. These studies propose that neoplastic osteoblast-like cells are responsible for the pathophysiological mineralization.
Significance of BMP Signalling in Osteoblastic Differentiation of Breast Cancer Cells
It was earlier reported that parathyroid hormone related protein (PTHrP) has a role in regulating pathological microcalcification in breast cancer [154]. However, detailed studies have not yet been conducted to show the mechanism for PTHrP-mediated mineralization. Emerging evidence suggests that BMP-2 might play a significant role in regulating breast cancer microcalcification [23, 71, 124, 155, 156].
BMPs are multifunctional growth factors that belong to the transforming growth factor-β (TGF-β) superfamily. Earlier studies established that BMPs are potent osteoinducers, and play a vital role in physiological and pathophysiological calcification of different tissues such as cartilage, bone, and arteries [157, 158]. BMPs can transduce signalling through canonical and non-canonical pathways to perform various physiological and pathological functions [159–171], which have been briefly described in Fig. 2.
Proposed molecular mechanism for microcalcification. BMPs transmit messages by canonical and non-canonical pathways to perform several physiological and pathological functions. Using non-canonical pathway (NCP), BMPs activate proliferative, cell survival, mitogenic signalling and induces EMT of epithelial breast cancer cells. Using canonical pathway (CP), BMPs activates Smad signalling to transcribe different transcription factors which eventually upregulate ALP and bone matrix proteins, involved in mineralization of transformed cells (EMT cells). BMP also increases MVs component TRPC channel and ALP. Subsequently, all proteins necessary for microcalcification formation accumulate within a microdomain of the membrane. This microdomain (enriched with these proteins) can be pinched out from the parental membrane, which results in the formation of MVs. The pH of MVs differs from the pH of the cytoplasm. Thus, at the appropriate pH, a monocrystal of HA forms, and then this MV is released into the extracellular matrix. This monocrystal acts as nucleus for the further HA deposition. Tumor cell derived cytokines such as MCP-1 and CSF-1 recruit macrophages at the tumor site; these macrophages further propagate this process by secreting MVs to the nucleation site of crystal. BMP also increases apoptosis, and the apoptotic bodies also accelerate the process of microcalcification
Recent findings by Cox et al. show that BMP-2 treatment potentiates osteogenic cocktail-induced mineralization in 4 T1 metastatic breast cancer cells [23, 71]. Similarly, another research group observed that inoculation of the R3230 rat mammary carcinoma cells overexpressing BMP-2 into the mammary fat pads resulted in breast tumors with microcalcification, as compared to the control group [155]. The same group also demonstrated that treatment with recombinant BMP-2 induced microcalcification in breast cancer tissue of all rats bearing tumors [156]. All these findings suggest that BMP-2 can induce microcalcification in breast cancer. Recently Scimeca et al., reported a key finding that BMP-2 expression was upregulated in infiltrating carcinoma with microcalcification as compared to infiltrating carcinoma without microcalcification, and these calcified infiltrating carcinoma tissues showed expression of both mesenchymal markers and osteoblastic proteins [124]. Based on these findings, it was proposed that a subpopulation of cancer cells which underwent EMT showed the osteoblast-like phenotype, a transition that is presumably driven by BMP-2 [124].
There is also evidence that BMP heightens the expression of transient receptor potential cation channel (TRPC) which may facilitate microcalcification by supplying Ca2+ ions to the cells/MVs [172]. Recent literature shows a positive association with serum BMP and cancer metastasis and/or advanced stage of cancer [173]. Many studies have demonstrated that BMPs inhibit cancer cell proliferation [174–177], but augment migration and invasion of breast cancer cells [178–181], presumably by inducing EMT [167, 182–186].
These findings suggest that BMP-2 not only induces EMT of epithelial breast cancer cells, but also can transdifferentiate EMT-cells to osteoblast-like cells. This subpopulation, which acquires osteoblastic properties, seems to be more competent for pathological microcalcification in breast cancer (schematically described in supplementary Figure S1).
Macrophage Recruitment Accelerates Microcalcification
Heterogeneous tumors consist of tumorigenic, non-tumorigenic, cancer stem cells, and non-cancer cells. Breast tumor cells secrete many inflammatory cytokines such as CCL2, CCL5 and CSF-1 [187, 188], which recruit macrophages to the tumor site, increasing the malignancy of cancers [189–191]. Moreover, metastatic breast cancer cells secrete more CSF-1 when compared to non-metastatic breast cancer cells [188]. Elevation of CSF-1 levels in human serum has been linked with the malignancy of different cancers including endometrial, breast, and ovarian carcinoma [192]. The elevation of CSF-1 results in dense macrophage infiltration to the tumor site [193]. These recruited macrophages, known as tumor associated macrophages (TAMs), play a pivotal role in microcalcification as they supply MVs to the nucleation centre of microcalcification [194]. Other studies also support this idea since breast biopsy samples were shown to have an accumulation of macrophages surrounding microcalcification [195]. Thus, these TAMs could provide additional support for the development of microcalcification in malignant breast tumors.
Proposed Mechanism of Microcalcification
Based on all the literature discussed above, we herein propose a mechanism that the accretion of microcalcification of breast cancer is preceded by a few specialized cells, which have undergone EMT, and also have acquired osteoblastic characteristics. These rare cells with mesenchymal characteristics, become osteoinductive in response to BMP, and function like osteoblasts which may also express NaPi-IIb transporter, NPP, TNAP, TRPC, and annexin channels [76, 79, 86, 87, 135, 196–198], to facilitate calcification. Finally, lipid rafts containing these protein molecules may be pinched out from the membrane to form MVs inside the cells. These MVs move to the extracellular environment, and unload the crystal molecules on the top of extracellular matrix proteins. Other MVs, along with Ca2+ and PO4 3− ions found in the extracellular fluid may support the propagation of crystal formation, which subsequently leads to microcalcification (Fig. 2).
BMPs sometime increase apoptosis of cancer cells, but these apoptotic bodies may, in turn, promote microcalcification [199]. BMPs obstruct tumor growth by inhibiting cancer cell proliferation. This infers that BMPs may have anticancer activity, but when the growth of cancer cells is halted, it may allow differentiation of epithelial cells to a mesenchymal phenotype (Supplementary Figure S1). Therefore, BMPs may augment an invasive phenotype, as well as the calcifying property of cancer cells by increasing by apoptotic bodies that promote microcalcification, and by inhibiting cell growth which may allow epithelial cells to undergo EMT. These cells may be transduced into osteoblast-like cells.
In addition, some cytokines such as CSF-1, CCL2 and CCL5 recruit macrophages to the site of microcalcification [189, 193]. These recruited macrophages might accelerate this pathophysiological mineralization by supplying MVs to the site of crystallization (Fig. 2).
Future Prospects
More basic and clinical research work is required to confirm the presence of microcalcification as a diagnostic and/or a prognostic marker for breast cancer progression and metastasis. In fact, only a causal link between the occurrence of microcalcification and malignancy of cancer has been shown. Thus, it has to be investigated whether the presence/occurrence of mineralization or microcalcification in aggressive cancer tissues is a consequence of the metastatic nature of cancerous tissues. A few studies support the positive role of HA in cancer progression [19, 20, 37]. However, more research is needed to define the function of HA in the regulation of invasiveness/malignancy of cancers. Since cancer cells having osteoblastic properties drive the calcification process, and BMPs are known potent osteoinductive agents, BMPs might promote the microcalcification process. What needs to be resolved is how epithelial cells gain osteoblastic properties. Furthermore, validation is required to know whether EMT is a prerequisite for gaining the osteoblast-like properties of cancer cells. The molecular mechanisms need to be elucidated to determine whether BMPs drive osteoblastic transdifferentiation of epithelial cancer cells followed by EMT or if it induces osteoblastic properties in EMT cells. Future studies will confirm if targeting microcalcification in breast cancer will be a promising therapeutic intervention. Breast cancer often occurs in postmenopausal women. At this age, the risk of osteoporosis is also quite high. Thus, a special strategy should be taken to design a therapeutic drug which prevents microcalcification of breast tissues without debilitating bone quality.
Abbreviations
- TRPC:
-
Transient receptor potential cation channel
- NPP1:
-
Nucleotide pyrophosphatase phosphodiesterase 1
- TNAP:
-
Tissue non-specific alkaline phosphatase
- HA:
-
Hydroxyapatite
- NTP:
-
Nucleoside triphosphate
- iPP:
-
Inorganic pyrophosphate
- iP:
-
Inorganic phosphate
- EMT:
-
Epithelial to mesenchymal transition
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Acknowledgment
Authors thank the Editors-in-Chief Prof. Russell C. Hovey (Department of Animal Science, University of California, Davis, USA) and the reviewers for their critical comments and suggestions. CCM is supported by UGC Grant [30-49/2014 (BSR)], DBT [6242 P9/RGCB/PMD/DBT/CCML/2015] and Central University of Rajasthan, India, and TS is supported by DST-INSPIRE fellowship [IF140765] provided by the Department of Science and Technology, India.
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Supplementary Fig. S1
BMPs as inducers of hydroxyapatite formation. BMPs are sourced in tumor microenvironment from different types of cells including breast tumor cells, cancer associated cells such as macrophages, and blood. BMPs molecules may act on the breast tumor cells to inhibit cell proliferation and to induce apoptosis of cancer cells. BMPs may also induce EMT in a few cancer cells. Cells which have undergone EMT attain osteoblast properties in response to BMP. These osteoblast cells secrete HA to the extracellular fluid spaces which results in microcalcification. Moreover, this process of HA formation is further accelerated by apoptotic bodies which may be produced due to the action of BMPs. Abbreviation: OB-Osteoblast, HA-Hydroxyapatite, EMT-Epithelial to mesenchymal transition. (TIFF 326 kb)
Supplementary Table S1
Detection of microcalcification in different tissues by different techniques. Abbreviations: HE-Hematoxylin & eosin, VKS-Von Kossa stain, PET-Positron emission tomography, US-Ultrasonography, LM-Light microscopy, SEM-Scanning electron microscopy, TEM-Transmission electron microscopy, CNB-Core needle biopsy, MRI-Magnetic resonance imaging, FTIR-Fourier transform infrared spectroscopy, DCIS-Ductal carcinoma in situ, IC-Invasive carcinoma, LCIS-Lobular carcinoma in situ, IDC-Invasive ductal carcinoma, ILC-Invasive lobular carcinoma, CT-Computed tomography. (DOCX 58 kb)
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Sharma, T., Radosevich, J.A., Pachori, G. et al. A Molecular View of Pathological Microcalcification in Breast Cancer. J Mammary Gland Biol Neoplasia 21, 25–40 (2016). https://doi.org/10.1007/s10911-015-9349-9
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DOI: https://doi.org/10.1007/s10911-015-9349-9