Raised mammographic density: causative mechanisms and biological consequences

Sherratt, Michael J.; McConnell, J. C.; Streuli, Charles

doi:10.1186/s13058-016-0701-9

Cited by 66 publications

(63 citation statements)

References 82 publications

(85 reference statements)

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“…Mammographic density is a strong predictor of breast cancer risk [53–55]. However, epidemiologic data linking ECM density and breast cancer aggression are inconsistent [56, 57].…”

Section: Discussionmentioning

confidence: 99%

Elevated collagen-I augments tumor progressive signals, intravasation and metastasis of prolactin-induced estrogen receptor alpha positive mammary tumor cells

et al. 2017

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BackgroundThe development and progression of estrogen receptor alpha positive (ERα+) breast cancer has been linked epidemiologically to prolactin. However, activation of the canonical mediator of prolactin, STAT5, is associated with more differentiated cancers and better prognoses. We have reported that density/stiffness of the extracellular matrix potently modulates the repertoire of prolactin signals in human ERα + breast cancer cells in vitro: stiff matrices shift the balance from the Janus kinase (JAK)2/STAT5 cascade toward pro-tumor progressive extracellular regulated kinase (ERK)1/2 signals, driving invasion. However, the consequences for behavior of ERα + cancers in vivo are not known.MethodsIn order to investigate the importance of matrix density/stiffness in progression of ERα + cancers, we examined tumor development and progression following orthotopic transplantation of two clonal green fluorescent protein (GFP) + ERα + tumor cell lines derived from prolactin-induced tumors to 8-week-old wild-type FVB/N (WT) or collagen-dense (col1a1 tm1Jae/+) female mice. The latter express a mutant non-cleavable allele of collagen 1a1 “knocked-in” to the col1a1 gene locus, permitting COL1A1 accumulation. We evaluated the effect of the collagen environment on tumor progression by examining circulating tumor cells and lung metastases, activated signaling pathways by immunohistochemistry analysis and immunoblotting, and collagen structure by second harmonic generation microscopy.ResultsERα + primary tumors did not differ in growth rate, histologic type, ERα, or prolactin receptor (PRLR) expression between col1a1 tm1Jae/+ and WT recipients. However, the col1a1 tm1Jae/+ environment significantly increased circulating tumor cells and the number and size of lung metastases at end stage. Tumors in col1a1 tm1Jae/+ recipients displayed reduced STAT5 activation, and higher phosphorylation of ERK1/2 and AKT. Moreover, intratumoral collagen fibers in col1a1 tm1Jae/+ recipients were aligned with tumor projections into the adjacent fat pad, perpendicular to the bulk of the tumor, in contrast to the collagen fibers wrapped around the more uniformly expansive tumors in WT recipients.ConclusionsA collagen-dense extracellular matrix can potently interact with hormonal signals to drive metastasis of ERα + breast cancers.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-017-0801-1) contains supplementary material, which is available to authorized users.

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“…Mammographic density is a strong predictor of breast cancer risk [53–55]. However, epidemiologic data linking ECM density and breast cancer aggression are inconsistent [56, 57].…”

Section: Discussionmentioning

confidence: 99%

Elevated collagen-I augments tumor progressive signals, intravasation and metastasis of prolactin-induced estrogen receptor alpha positive mammary tumor cells

et al. 2017

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“…In general, measured stiffness increases as length scale decreases so that organs and tissues are less stiff than their component molecules . In addition, cells sense the stiffness of their local (μm and nm) environment and the importance of local stiffness in mediating cell phenotype is clear from studies in cancer biology where stiffness influences cancer progression …”

Section: Current State Of Knowledgementioning

confidence: 99%

How stiff is skin?

Graham

McConnell

Limbert

et al. 2019

Experimental Dermatology

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The measurement of the mechanical properties of skin (such as stiffness, extensibility and strength) is a key step in characterisation of both dermal ageing and disease mechanisms and in the assessment of tissue‐engineered skin replacements. However, the biomechanical terminology and plethora of mathematical analysis approaches can be daunting to those outside the field. As a consequence, mechanical studies are often inaccessible to a significant proportion of the intended audience. Furthermore, devices for the measurement of skin function in vivo generate relative values rather than formal mechanical measures, therefore limiting the ability to compare studies. In this viewpoint essay, we discuss key biomechanical concepts and the influence of technical and biological factors (including the nature of the testing apparatus, length scale, donor age and anatomical site) on measured mechanical properties such as stiffness. Having discussed the current state‐of‐the‐art in macro‐mechanical and micromechanical measuring techniques and in mathematical and computational modelling methods, we then make suggestions as to how these approaches, in combination with 3D X‐ray imaging and mechanics methods, may be adopted into a single strategy to characterise the mechanical behaviour of skin.

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“…Genome‐wide association studies (GWAS) have identified variants at specific genetic loci associated with mammographic density, and about 15% of the genetic variants known to be associated with breast cancer risk are also associated with mammographic density measures, although they explain only a small fraction of the latter. Despite these known determinants, the molecular mechanisms underlying variation in mammographic density are not well understood, nor is how mammographic density translates into breast cancer risk at the biological level …”

Section: Introductionmentioning

confidence: 99%

“…Despite these known determinants, the molecular mechanisms underlying variation in mammographic density are not well understood, nor is how mammographic density translates into breast cancer risk at the biological level. 7 DNA methylation, a process whereby typically a methyl group is added to a cytosine-guanine dinucleotide, plays an important role in modulating gene expression without changing the underlying DNA sequence. There is increasing evidence that blood DNA methylation is associated with variation in traits or disease risks, and also considerable interest in determining if there is any relationship between blood DNA methylation and breast cancer risk.…”

Section: Introductionmentioning

confidence: 99%

Genome‐wide association study of peripheral blood DNA methylation and conventional mammographic density measures

Dugué

Baglietto

et al. 2019

Intl Journal of Cancer

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Age‐ and body mass index (BMI)‐adjusted mammographic density is one of the strongest breast cancer risk factors. DNA methylation is a molecular mechanism that could underlie inter‐individual variation in mammographic density. We aimed to investigate the association between breast cancer risk‐predicting mammographic density measures and blood DNA methylation. For 436 women from the Australian Mammographic Density Twins and Sisters Study and 591 women from the Melbourne Collaborative Cohort Study, mammographic density (dense area, nondense area and percentage dense area) defined by the conventional brightness threshold was measured using the CUMULUS software, and peripheral blood DNA methylation was measured using the HumanMethylation450 (HM450) BeadChip assay. Associations between DNA methylation at >400,000 sites and mammographic density measures adjusted for age and BMI were assessed within each cohort and pooled using fixed‐effect meta‐analysis. Associations with methylation at genetic loci known to be associated with mammographic density were also examined. We found no genome‐wide significant (p < 10−7) association for any mammographic density measure from the meta‐analysis, or from the cohort‐specific analyses. None of the 299 methylation sites located at genetic loci associated with mammographic density was associated with any mammographic density measure after adjusting for multiple testing (all p > 0.05/299 = 1.7 × 10−4). In summary, our study did not find evidence for associations between blood DNA methylation, as measured by the HM450 assay, and conventional mammographic density measures that predict breast cancer risk.

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Raised mammographic density: causative mechanisms and biological consequences

Cited by 66 publications

References 82 publications

Elevated collagen-I augments tumor progressive signals, intravasation and metastasis of prolactin-induced estrogen receptor alpha positive mammary tumor cells

Elevated collagen-I augments tumor progressive signals, intravasation and metastasis of prolactin-induced estrogen receptor alpha positive mammary tumor cells

How stiff is skin?

Genome‐wide association study of peripheral blood DNA methylation and conventional mammographic density measures

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