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Mapping the genetic basis of breast microcalcifications and their role in metastasis.

ABSTRACT: Breast cancer screening and early stage diagnosis is typically performed by X-ray mammography, which detects microcalcifications. Despite being one of the most reliable features of nonpalpable breast cancer, the processes by which these microcalcifications form are understudied and largely unknown. In the current work, we have investigated the genetic drivers for the formation of microcalcifications in breast cancer cell lines, and have investigated their involvement in disease progression. We have shown that stable silencing of the Osteopontin (OPN) gene decreased the formation of hydroxyapatite in MDA-MB-231 breast cancer cells in response to osteogenic cocktail. In addition, OPN silencing reduced breast cancer cell migration. Furthermore, breast cancer cells that had spontaneously metastasized to the lungs in a mouse model of breast cancer had largely elevated OPN levels, while circulating tumor cells in the same mouse model contained intermediately increased OPN levels as compared to parental cells. The observed dual roles of the OPN gene reveal the existence of a direct relationship between calcium deposition and the ability of breast cancer cells to metastasize to distant organs, mediated by common genetic factors.

SUBMITTER: Rizwan A

PROVIDER: S-EPMC6056534 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Mapping the genetic basis of breast microcalcifications and their role in metastasis.

Rizwan Asif A Paidi Santosh Kumar SK Zheng Chao C Cheng Menglin M Barman Ishan I Glunde Kristine K

Scientific reports 20180723 1

Breast cancer screening and early stage diagnosis is typically performed by X-ray mammography, which detects microcalcifications. Despite being one of the most reliable features of nonpalpable breast cancer, the processes by which these microcalcifications form are understudied and largely unknown. In the current work, we have investigated the genetic drivers for the formation of microcalcifications in breast cancer cell lines, and have investigated their involvement in disease progression. We h ...[more]

PMID: 30038419

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Project description:BackgroundBreast microcalcifications are key diagnostically significant radiological features for localisation of malignancy. This study explores the hypothesis that breast calcification composition is directly related to the local tissue pathological state.MethodsA total of 236 human breast calcifications from 110 patients were analysed by mid-Fouries transform infrared (FTIR) spectroscopy from three different pathology types (112 invasive carcinoma (IC), 64 in-situ carcinomas and 60 benign). The biochemical composition and the incorporation of carbonate into the hydroxyapatite lattice of the microcalcifications were studied by infrared microspectroscopy. This allowed the spectrally identified composition to be directly correlated with the histopathology grading of the surrounding tissue.ResultsThe carbonate content of breast microcalcifications was shown to significantly decrease when progressing from benign to malignant disease. In this study, we report significant correlations (P<0.001) between microcalcification chemical composition (carbonate content and protein matrix : mineral ratios) and distinct pathology grades (benign, in-situ carcinoma and ICs). Furthermore, a significant correlation (P<0.001) was observed between carbonate concentrations and carcinoma in-situ sub-grades. Using the two measures of pathology-specific calcification composition (carbonate content and protein matrix : mineral ratios) as the inputs to a two-metric discriminant model sensitivities of 79, 84 and 90% and specificities of 98, 82 and 96% were achieved for benign, ductal carcinoma in situ and invasive malignancies, respectively.ConclusionsWe present the first demonstration of a direct link between the chemical nature of microcalcifications and the grade of the pathological breast disease. This suggests that microcalcifications have a significant association with cancer progression, and could be used for future objective analytical classification of breast pathology. A simple two-metric model has been demonstrated, more complex spectral analysis may yeild greater discrimination performance. Furthermore there appears to be a sequential progression of calcification composition.

Project description:Breast density and microcalcifications are strongly associated with the risk of breast cancer. However, few studies have evaluated the combined association between these two factors and breast cancer risk. We investigated the association between breast density, microcalcifications, and risk of breast cancer. This cohort study included 3,910,815 women aged 40-74 years who were screened for breast cancer between 2009 and 2010 and followed up until 2020. The National Health Insurance Service database includes national health-screening results from the national breast cancer screening program, which is an organized screening program provided every 2 years for all women aged 40 years or older. Breast density was assessed based on the Breast Imaging Reporting and Data System (BI-RADS) 4th edition, mostly through visual assessment by radiologists. The presence or absence of microcalcifications was obtained from the mammographic results. Cox proportional hazard regression for breast cancer risk was used to estimate hazard ratios (aHRs) adjusted for breast cancer risk factors. A total of 58,315 women developed breast cancer during a median follow-up of 10.8 years. Women with breast cancer had a higher proportion of microcalcifications than women without breast cancer (0.9% vs. 0.3%). After adjusting for breast density, women with microcalcification had a 3.07-fold (95% confidence interval [CI] 2.82-3.35) increased risk of breast cancer compared to women without microcalcification. The combined association between microcalcification and breast density dramatically increased the risk of breast cancer, corresponding to a higher level of breast density. Among postmenopausal women, the highest risk group was women with BI-RADS 4 and microcalcification. These women had more than a sevenfold higher risk than women with BI-RADS 1 and non-microcalcification (aHR, 7.26; 95% CI 5.01-10.53). Microcalcification is an independent risk factor for breast cancer, and its risk is elevated when combined with breast density.

Dataset Information

Mapping the genetic basis of breast microcalcifications and their role in metastasis.

Publications

Mapping the genetic basis of breast microcalcifications and their role in metastasis.

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