Biological Mechanisms and Therapeutic Opportunities in Mammographic Density and Breast Cancer Risk

Archer, Maddison; Dasari, Pallave; Evdokiou, Andreas; Ingman, Wendy V.

doi:10.3390/cancers13215391

Cited by 12 publications

(7 citation statements)

References 208 publications

(263 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Understanding, and correctly classifying the driving components of MD (reviewed in ref. 57 ) into those that influence breast cancer risk, and using those for future studies could increase results precision and the degree of mediation detected. Motivated by a recent study that explored a similarly heterogenous effect of IGF-1 on type 2 diabetes using MR-Clust and pathway analysis 58 , in our work, we attempted to characterise pathways that may be underlying the identified positive and negative effect clusters.…”

Section: Discussionmentioning

confidence: 99%

Mammographic density mediates the protective effect of early-life body size on breast cancer risk

Vabistsevits,

Davey Smith,

Richardson

et al. 2024

Nat Commun

View full text Add to dashboard Cite

The unexplained protective effect of childhood adiposity on breast cancer risk may be mediated via mammographic density (MD). Here, we investigate a complex relationship between adiposity in childhood and adulthood, puberty onset, MD phenotypes (dense area (DA), non-dense area (NDA), percent density (PD)), and their effects on breast cancer. We use Mendelian randomization (MR) and multivariable MR to estimate the total and direct effects of adiposity and age at menarche on MD phenotypes. Childhood adiposity has a decreasing effect on DA, while adulthood adiposity increases NDA. Later menarche increases DA/PD, but when accounting for childhood adiposity, this effect is attenuated. Next, we examine the effect of MD on breast cancer risk. DA/PD have a risk-increasing effect on breast cancer across all subtypes. The MD SNPs estimates are heterogeneous, and additional analyses suggest that different mechanisms may be linking MD and breast cancer. Finally, we evaluate the role of MD in the protective effect of childhood adiposity on breast cancer. Mediation MR analysis shows that 56% (95% CIs [32%–79%]) of this effect is mediated via DA. Our finding suggests that higher childhood adiposity decreases mammographic DA, subsequently reducing breast cancer risk. Understanding this mechanism is important for identifying potential intervention targets.

show abstract

Section: Discussionmentioning

confidence: 99%

Mammographic density mediates the protective effect of early-life body size on breast cancer risk

Vabistsevits,

Davey Smith,

Richardson

et al. 2024

Nat Commun

View full text Add to dashboard Cite

show abstract

“…There is also a strong possibility that not all contributors to MD influence breast cancer risk. Understanding, and correctly classifying the driving components of MD (reviewed in [57]) into those that influence breast cancer risk, and using those for future studies could increase results precision and the degree of mediation detected. Motivated by a recent study that explored a similarly heterogenous effect of IGF-1 on type 2 diabetes using MR-Clust and pathway analysis [58], in our work, we attempted to characterise pathways that may be underlying the identified positive and negative effect clusters.…”

Section: Discussionmentioning

confidence: 99%

The mediating role of mammographic density in the protective effect of early-life adiposity on breast cancer risk: a multivariable Mendelian randomization study

Vabistsevits,

Smith,

Richardson

et al. 2023

Preprint

View full text Add to dashboard Cite

Observational studies suggest that mammographic density (MD) may have a role in the unexplained protective effect of childhood adiposity on breast cancer risk. Here, we investigated a complex and interlinked relationship between puberty onset, adiposity, MD, and their effects on breast cancer using Mendelian randomization (MR).We estimated the effects of childhood and adulthood adiposity, and age at menarche on MD phenotypes (dense area (DA), non-dense area (NDA), percent density (PD)) using MR and multivariable MR (MVMR), allowing us to disentangle their total and direct effects. Next, we examined the effect of MD on breast cancer risk, including risk of molecular subtypes, and accounting for genetic pleiotropy. Finally, we used MVMR to evaluate whether the protective effect of childhood adiposity on breast cancer was mediated by MD.Childhood adiposity had a strong inverse effect on mammographic DA, while adulthood adiposity increased NDA. Later menarche had an effect of increasing DA and PD, but when accounting for childhood adiposity, this effect attenuated to the null. DA and PD had a risk-increasing effect on breast cancer across all subtypes. The MD single-nucleotide polymorphism (SNP) estimates were extremely heterogeneous, and examination of the SNPs suggested different mechanisms may be linking MD and breast cancer. Finally, MR mediation analysis estimated that 56% (95% CIs [32% - 79%]) of the childhood adiposity effect on breast cancer risk was mediated via DA.In this work, we sought to disentangle the relationship between factors affecting MD and breast cancer. We showed that higher childhood adiposity decreases mammographic DA, which subsequently leads to reduced breast cancer risk. Understanding this mechanism is of great importance for identifying potential targets of intervention, since advocating weight gain in childhood would not be recommended.

show abstract

“…High breast density appears on a mammogram as white areas and signifies a high abundance of fibroglandular tissue in the breast in proportion to the abundance of adipose tissue. Breast density is typically quantified as ‘percent mammographic density’, calculated as the ratio of the area of dense breast tissue to the total area of breast tissue [ 1 , 2 ]. Breast density impacts upon both breast cancer risk and the early detection of breast cancer on a mammogram and has become a major focus of interest within the medical, scientific, and broader community [ 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

Factors Associated with Increased Knowledge about Breast Density in South Australian Women Undergoing Breast Cancer Screening

Bhattacharjee,

Walsh,

Dasari

et al. 2024

Cancers

Self Cite

View full text Add to dashboard Cite

Background: There is growing awareness of breast density in women attending breast cancer screening; however, it is unclear whether this awareness is associated with increased knowledge. This study aims to evaluate breast density knowledge among Australian women attending breast cancer screening. Method: This cross-sectional study was conducted on women undergoing breast cancer screening at The Queen Elizabeth Hospital Breast/Endocrine outpatient department. Participants were provided with a questionnaire to assess knowledge, awareness, and desire to know their own breast density. Result: Of the 350 women who participated, 61% were familiar with ‘breast density’ and 57% had ‘some knowledge’. Prior breast density notification (OR = 4.99, 95% CI = 2.76, 9.03; p = 0.004), awareness (OR = 4.05, 95% CI = 2.57, 6.39; p = 0.004), younger age (OR = 0.97, 95% CI = 0.96, 0.99; p = 0.02), and English as the language spoken at home (OR = 3.29, 95% CI = 1.23, 8.77; p = 0.02) were independent predictors of ‘some knowledge’ of breast density. A significant proportion of participants (82%) expressed desire to ascertain their individual breast density. Conclusions: While knowledge of breast density in this Australian cohort is generally quite low, we have identified factors associated with increased knowledge. Further research is required to determine optimal interventions to increase breast density knowledge.

show abstract

Biological Mechanisms and Therapeutic Opportunities in Mammographic Density and Breast Cancer Risk

Cited by 12 publications

References 208 publications

Mammographic density mediates the protective effect of early-life body size on breast cancer risk

Mammographic density mediates the protective effect of early-life body size on breast cancer risk

The mediating role of mammographic density in the protective effect of early-life adiposity on breast cancer risk: a multivariable Mendelian randomization study

Factors Associated with Increased Knowledge about Breast Density in South Australian Women Undergoing Breast Cancer Screening

Contact Info

Product

Resources

About