# Targeting RANK Pathway in Mammographic Density and Primary Breast Cancer Prevention

> **NIH NIH R37** · WASHINGTON UNIVERSITY · 2020 · $627,245

## Abstract

ABSTRACT
Women with dense breasts on mammograpm have a 4-6-fold increased risk of breast cancer. A sizeable
proportion of premenopausal breast cancer cases (39%) are attributable to having dense breasts.
Observational and clinical trial data have shown that a decrease in breast density translates to a reduction in
breast cancer incidence. Hence, interventions to reduce breast density could prevent breast cancer. However,
adult dietary and lifestyle modifications have not been shown to reduce mammographic density. Therefore,
identifying a pathway that can be targeted to reduce breast density and breast cancer incidence is crucial. The
receptor activator of nuclear factor-κB (RANK) pathway regulates the development of the lobulo-alveolar
mammary structures, activates downstream signaling cascades involved in breast cancer and is the major
mediator of progesterone-driven expansion of mammary stem cells. The RANK pathway is associated with
mammographic density and breast cancer risk. This has led to a strong interest in inhibiting RANK ligand
(RANKL) signaling to prevent breast cancer. Nevertheless, clinical trial data providing definitive evidence that
would allow the adoption of RANKL inhibition in reducing dense breasts and prevent breast cancer are not yet
available. We, thereby, propose to (i) perform a randomized clinical trial to quantify the effect of RANKL
inhibition with denosumab on mammographic density in high-risk premenopausal women with dense breasts
(Primary Aim); (ii) determine the effect of RANKL inhibition on breast tissue RANK, progesterone-regulated
pathway gene expression, and related biomarkers associated with breast cancer risk (Secondary Aim).
Approach: Study participants will be randomized (1:1) to an intervention (N=116) or placebo arm (N=116).
Intervention: The intervention arm will receive two subcutaneous injections of denosumab (60 mg), one at
baseline, and a second at 6 months. The placebo arm will receive two subcutaneous placebo injections at
baseline, and 6 months. We will use Volpara software to assess mammographic density at baseline, and 12
months. Volpara quantifies volumetric measures of density; volumetric percent density (VPD) allowing us to
test differences in change in mammographic density at 12 months among women assigned to intervention vs.
placebo. Study population: 232 women undergoing annual screening mammography at the Siteman Cancer
Center (SCC), St. Louis, MO. Inclusion criteria: (i) premenopausal; (ii) ≥40 years of age; (iii) dense breasts
(volumetric percent density ≥7.5% on Volpara, equivalent to BI-RADS Category C; (iv) have an increased risk
of breast cancer (e.g. positive history of breast cancer in a first-degree relative, non-BRCA susceptibility
genes). Target population: Annually, >3,500 premenopausal women with dense breasts aged ≥40 years
undergo screening mammogram at the SCC, hence, we are confident of reaching our recruitment goals.
Impact: Study findings could open up additional thera...

## Key facts

- **NIH application ID:** 9989082
- **Project number:** 5R37CA235602-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Adetunji T Toriola
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $627,245
- **Award type:** 5
- **Project period:** 2019-08-05 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9989082

## Citation

> US National Institutes of Health, RePORTER application 9989082, Targeting RANK Pathway in Mammographic Density and Primary Breast Cancer Prevention (5R37CA235602-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9989082. Licensed CC0.

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