Role of malignant microcalcifications in HER2+ breast cancer cellsZhang, He (2022) Role of malignant microcalcifications in HER2+ breast cancer cells. Master's Thesis, University of Pittsburgh. (Unpublished)
AbstractBreast microcalcifications (MCs) are tiny calcium deposits that appear on mammograms and are commonly used as a diagnostic tool for nonpalpable early-stage breast cancer. Based on the chemical composition, MCs are categorized into type I calcium oxalate (OX, benign); and type II calcium phosphate, mainly hydroxyapatite (HA, malignant) microcalcifications. Clinical studies show that calcium phosphate MCs are more likely to be present in human epidermal growth factor receptor 2 (HER2) positive breast cancer. Patient biopsies also show that the breast cancer cells surrounding these MCs express higher levels of mesenchymal markers and bone markers, suggesting the possibility of epithelial to mesenchymal transition (EMT) and bone mimicry. Abnormal inorganic phosphate serum concentration caused by hyperphosphatemia or high phosphate diet is associated to calcifications in multiple soft tissues. Interestingly, studies unrelated to MCs have shown higher phosphate concentration in breast tumor microenvironment. Growth rate hypothesis also indicates higher local phosphate concentration in tumor microenvironment to sustain high proliferation rate of tumor cells. Thus, it is plausible that the presence of malignant calcium phosphate MCs creates phosphate-rich microenvironment in tumor. Inorganic phosphate concentration is regulated by sodium-dependent phosphate (Na-Pi) cotransporters, namely SLC34A2, SLC20A1 (Pit1) and SLCA0A2 (Pit2). In particular, SLC34A2 regulates the phosphate concentration in multiple lumen fluids including mammary glands and maintains phosphate homeostasis, whereas the SLC20 family regulates cellular phosphate concentration with a potential role in phosphate sensing. Elevated levels of Pi and Na-Pi co-transporters are known to play a critical role during bone development and bone diseases. Several studies have shown abnormal expression of Na-Pi cotransporters in multiple tumor types and pathological calcification. However, not much is known about the effect of malignant calcium phosphate MCs on regulating the expression of Na-Pi cotransporter expression in breast cancer cells. In this study, we hypothesized that the malignant calcium phosphate MCs can create a phosphate rich microenvironment, which may alter Pi transport and expression of Na-Pi cotransporters in breast cancer cells and induce EMT process and bone mimicry in the surrounding breast cancer cells. To test our hypothesis, we selected two breast cancer cell lines with different ER, HER2 status: BT474 (ER+, HER2+) and SUM225 (ER-, HER2+), and then compared expression of Na-Pi co-transporters with normal human breast cancer epithelial cells MCF10A (ER-, HER2-). Then, we fabricated extracellular matrix (ECM)-mimicking soft hydrogels (ECM-mimics) to deposit and recapitulate chemical composition of benign (OX) and malignant (HA) MCs found in breast cancer patients. In conclusion, this study indicates that presence of malignant MCs may alter expression of Na-Pi co-transporters, and this may be dependent on the ER or HER2 status of the cancer cells. Share
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