Mammographically dense human breast tissue stimulates MCF10DCIS.com progression to invasive lesions and metastasis

Abstract

BackgroundHigh mammographic density (HMD) not only confers a significantly increased risk of breast cancer (BC) but also is associated with BCs of more advanced stages. However, it is unclear whether BC progression and metastasis are stimulated by HMD. We investigated whether patient-derived HMD breast tissue could stimulate the progression of MCF10DCIS.com cells compared with patient-matched low mammographic density (LMD) tissue.MethodsSterile breast specimens were obtained immediately after prophylactic mastectomy from high-risk women (n = 10). HMD and LMD regions of each specimen were resected under radiological guidance. Human MCF10DCIS.com cells, a model of ductal carcinoma in situ (DCIS), were implanted into silicone biochambers in the groins of severe combined immunodeficiency mice, either alone or with matched LMD or HMD tissue (1:1), and maintained for 6 weeks. We assessed biochamber weight as a measure of primary tumour growth, histological grade of the biochamber material, circulating tumour cells and metastatic burden by luciferase and histology. All statistical tests were two-sided.ResultsHMD breast tissue led to increased primary tumour take, increased biochamber weight and increased proportions of high-grade DCIS and grade 3 invasive BCs compared with LMD. This correlated with an increased metastatic burden in the mice co-implanted with HMD tissue.ConclusionsOur study is the first to explore the direct effect of HMD and LMD human breast tissue on the progression and dissemination of BC cells in vivo. The results suggest that HMD status should be a consideration in decision-making for management of patients with DCIS lesions.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-016-0767-4) contains supplementary material, which is available to authorized users.

The origins of breast cancer associated with mammographic density: a testable biological hypothesis

“…Radiologically dense human breast tissue obtained from mastectomy specimens has been shown to promote the growth and progression of human carcinoma in situ xenografts in immunodeficient mice [ 62 ]. The biological properties shown in Table 1 have all, with the exception of collagen density, been observed in human cells or tissues, but only three (proteoglycan expression, matrix metalloproteinase 3 [MMP-3], and CD36 expression) have been examined to date in relation to PMD.…”

T1‐based sensing of mammographic density using single‐sided portable NMR

“…Slices of breast tissue were resected using sterile technique by pathologists immediately after the completion of surgery. These methods had been detailed in our previous work . In brief, excised tissues were transported on ice to the respective pathology suites and assessed for abnormalities after routine cranio‐caudal slicing using sterile procedures.…”

Looking beyond the mammogram to assess mammographic density: A narrative review

“…High BPE prior to neoadjuvant chemotherapy (NAC) for pre-identified lesions has also been significantly associated with a poorer recurrence-free survival, where high BPE on pre-NAC MRI (hazard ratio [HR] = 3.851, p = 0.006) and triple-negative cancer (HR = 3.192, p = 0.002) were independent factors associated with worse regression free survival [24,94]. Several studies have shown that higher MD status also promoted BC progression [25,35,91], and we have recently provided experimental evidence for this [57].…”