Dang Donna, Prasad Hari, Rao Rajini
Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
Mol Carcinog. 2017 Nov;56(11):2474-2485. doi: 10.1002/mc.22695. Epub 2017 Jul 28.
Calcification of the breast is often an outward manifestation of underlying molecular changes that drive carcinogenesis. Up to 50% of all non-palpable breast tumors and 90% of ductal carcinoma in situ present with radiographically dense mineralization in mammographic scans. However, surprisingly little is known about the molecular pathways that lead to microcalcifications in the breast. Here, we report on a rapid and quantitative in vitro assay to monitor microcalcifications in breast cancer cell lines, including MCF7, MDA-MB-231, and Hs578T. We show that the Secretory Pathway Ca -ATPases SPCA1 and SPCA2 are strongly induced under osteogenic conditions that elicit microcalcifications. SPCA gene expression is significantly elevated in breast cancer subtypes that are associated with microcalcifications. Ectopic expression of SPCA genes drives microcalcifications and is dependent on pumping activity. Conversely, knockdown of SPCA expression significantly attenuates formation of microcalcifications. We propose that high levels of SPCA pumps may initiate mineralization in the secretory pathway by elevating luminal Ca . Our new findings offer mechanistic insight and functional implications on a widely observed, yet poorly understood radiographic signature of breast cancer.
乳腺钙化通常是驱动致癌作用的潜在分子变化的外在表现。在所有不可触及的乳腺肿瘤中，高达50%以及90%的导管原位癌在乳房X线扫描中呈现出放射学上致密的矿化。然而，令人惊讶的是，对于导致乳腺微钙化的分子途径知之甚少。在此，我们报告了一种快速且定量的体外检测方法，用于监测乳腺癌细胞系（包括MCF7、MDA-MB-231和Hs578T）中的微钙化。我们发现，分泌途径Ca-ATP酶SPCA1和SPCA2在引发微钙化的成骨条件下被强烈诱导。SPCA基因表达在与微钙化相关的乳腺癌亚型中显著升高。SPCA基因的异位表达驱动微钙化，并且依赖于泵浦活性。相反，SPCA表达的敲低显著减弱微钙化的形成。我们提出，高水平的SPCA泵可能通过升高管腔钙浓度在分泌途径中引发矿化。我们的新发现为一种广泛观察到但了解甚少的乳腺癌放射学特征提供了机制性见解和功能意义。
