Abstract
The expression of the melanoma/cancer-testis antigen MAGEC2/CT10 is restricted to germline cells, but like most cancer-testis antigens, it is frequently upregulated in advanced breast tumors and other malignant tumors. However, the physiological cues that trigger the expression of this gene during malignancy remain unknown. Given that malignant breast cancer is often associated with skeletal metastasis and co-morbidities such as cancer-induced hypercalcemia, we evaluated the effect of high Ca2+ on the calcium-sensing receptor (CaSR) and potential mechanisms underlying the survival of triple-negative breast cancer (TNBC) cells at high Ca2+. We show that chronic exposure of TNBC cells to high Ca2+ decreased the sensitivity of CaSR to Ca2+ but stimulated tumor cell growth and migration. Furthermore, high extracellular Ca2+ also stimulated the expression of early response genes such as FOS/FOSB and a unique set of genes associated with malignant tumors, including MAGEC2. We further show that the MAGEC2 proximal promoter is Ca2+ inducible and that FOS/FOSB binds to this promoter in a Ca2+- dependent manner. Finally, downregulation of MAGEC2 strongly inhibited the growth of TNBC cells in vitro. These data suggest for the first time that MAGEC2 is a high Ca2+ inducible gene and that aberrant expression of MAGEC2 in malignant TNBC tissues is at least in part mediated by an increase in circulating Ca2+ via the AP-1 transcription factor.
Highlights
Triple-negative breast cancer (TNBC) remains the most aggressive and hard-to-treat breast cancer subtype due in part to lack of estrogen and progesterone receptors (ER, PR), as well as the human epidermal growth factor receptor 2 (HER2)
This study suggests that the aberrant expression of MAGEC2 and presumably related cancer-testis antigens in malignant solid tumors is triggered at least in part by the gradual increase in circulating Ca2+ that develops as breast cancer progresses to more malignant stages
In the studies described 3.0 and 5.0 mM Ca2+ concentrations were routinely used as high Ca2+ for triple-negative breast cancer (TNBC) cells
Summary
Triple-negative breast cancer (TNBC) remains the most aggressive and hard-to-treat breast cancer subtype due in part to lack of estrogen and progesterone receptors (ER, PR), as well as the human epidermal growth factor receptor 2 (HER2). One of the most debilitating systemic cancer-associated changes that develop as breast and other solid cancers progress to more malignant and metastases-prone disease stages, is cancer-induced hypercalcemia (CIH) Even though frequently diagnosed as mild or non-lifethreatening, high circulating Ca2+ levels (>10.3 mg/dL) in breast cancer patients have been shown to be associated with aggressive tumors in premenopausal women [9] and larger tumors in postmenopausal women [10]. While this suggests that hypercalcemia drives breast cancer progression, this notion and the underlying mechanisms remain poorly understood. At the center of the Ca2+ sensing/signaling system is the ubiquitous cell surface Ca2+ sensor, the calcium-sensing receptor (CaSR), which is activated by slight increases in extracellular Ca2+ as well as other divalent cations and plays a central role in Ca2+
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