Principal Investigator

Adetunji T.
Toriola
Awardee Organization

Washington University
United States

Fiscal Year
2018
Activity Code
R21
Project End Date

RANK PATHWAY AND MAMMOGRAPHIC DENSITY IN MID-LIFE WOMEN

A very dense breast is one of the strongest risk factors for breast cancer. Close to 2 million women aged 50-64 years have extremely dense breast. It is estimated that 28% of breast cancer cases are attributable to increased breast density. Compared with other breast cancer risk factors that confer similar magnitude of risk (age, atypia on breast biopsy and highly penetrant breast cancer susceptibility genes), breast density is modifiable. A decrease in breast density over time is associated with decreased risk of breast cancer. Hence, strategies to reduce breast density could present a path to targeted prevention of breast cancer in many midlife women. However, there is very limited knowledge on how to modify breast density or biomarkers that can be targeted in reducing breast density. Recent seminal discoveries have identified that receptor activator of nuclear factor-κB (RANK) pathway plays a crucial role in the development of a functional lactating mammary gland as well as regulating mammary epithelial cells. Further, RANK ligand (RANKL) signaling is a major mediator of progesterone-induced proliferation of mammary epithelial cells and disruption of RANKL signaling attenuates progestin-driven mammary epithelial cell proliferation. Therefore, RANKL inhibition could provide a path to reducing breast density and breast cancer incidence in women with increased breast density. A well-tolerated RANKL inhibitor (denosumab) is already in clinical use for treating postmenopausal osteoporosis, but this has not been applied in primary prevention of breast cancer. Its ability to effectively inhibit RANKL signaling could allow for a novel approach to breast cancer prevention. In this proposal, we will investigate the association of the RANK pathway (circulating levels and genetic polymorphisms) with percent mammographic density in midlife women (50-64). We will also investigate factors that influence these women's intent to use a new chemopreventive agent. Study participants (N=398) will be recruited among women undergoing annual screening mammogram at the Breast Health Center (BHC), Washington University School of Medicine (WUSM), St. Louis. Blood draw will take place on the day of screening mammogram. A detailed reproductive and lifestyle questionnaire will also be completed. We will use Volpara software to assess percent breast density. Volpara permits robust quantitative analysis of breast density. Our proposal is innovative and could demonstrate novel, functionally important mechanistic associations with mammographic density. Importantly, it could provide essential information for the launch of trials targeting RANKL signaling in the primary prevention of breast cancer among mid-life women with very dense breast. 1

Publications

  • Han Y, Berkey CS, Herman CR, Appleton CM, Alimujiang A, Colditz GA, Toriola AT. Adiposity Change Over the Life Course and Mammographic Breast Density in Postmenopausal Women. Cancer prevention research (Philadelphia, Pa.). 2020 May;13(5):475-482. Epub 2020 Feb 26. PMID: 32102947
  • Han Y, Lee CT, Xu S, Mi X, Phillip CR, Salazar AS, Rakhmankulova M, Toriola AT. Medication use and mammographic breast density. Breast cancer research and treatment. 2021 Sep;189(2):585-592. Epub 2021 Jul 1. PMID: 34196899
  • Han Y, Colditz GA, Toriola AT. Changes in adiposity over the life course and gene expression in postmenopausal women. Cancer medicine. 2022 Jul;11(13):2699-2710. Epub 2022 Mar 19. PMID: 35304837
  • Akinjiyan FA, Adams A, Xu S, Wang M, Toriola AT. Plasma Growth Factor Gene Expression and Mammographic Breast Density in Postmenopausal Women. Cancer prevention research (Philadelphia, Pa.). 2022 Jun 2;15(6):391-398. PMID: 35288741
  • Toriola AT, Appleton CM, Zong X, Luo J, Weilbaecher K, Tamimi RM, Colditz GA. Circulating Receptor Activator of Nuclear Factor-κB (RANK), RANK ligand (RANKL), and Mammographic Density in Premenopausal Women. Cancer prevention research (Philadelphia, Pa.). 2018 Dec;11(12):789-796. Epub 2018 Oct 23. PMID: 30352839
  • Keller KG, Toriola AT, Kraenzle Schneider J. Women's Health Beliefs and Intention to Use Chemoprevention for Breast Cancer. Oncology nursing forum. 2023 Aug 17;50(5):611-623. PMID: 37677763
  • Mintz R, Wang M, Xu S, Colditz GA, Markovic C, Toriola AT. Hormone and receptor activator of NF-κB (RANK) pathway gene expression in plasma and mammographic breast density in postmenopausal women. Breast cancer research : BCR. 2022 Apr 14;24(1):28. PMID: 35422057
  • Keller KG, Toriola AT, Schneider JK. The relationship between cancer fatalism and education. Cancer causes & control : CCC. 2021 Feb;32(2):109-118. Epub 2020 Nov 5. PMID: 33151430
  • Moore JX, Han Y, Appleton C, Colditz G, Toriola AT. Determinants of Mammographic Breast Density by Race Among a Large Screening Population. JNCI cancer spectrum. 2020 Feb 26;4(2):pkaa010. doi: 10.1093/jncics/pkaa010. eCollection 2020 Apr. PMID: 32373777
  • Alimujiang A, Imm KR, Appleton CM, Colditz GA, Berkey CS, Toriola AT. Adiposity at Age 10 and Mammographic Density among Premenopausal Women. Cancer prevention research (Philadelphia, Pa.). 2018 May;11(5):287-294. Epub 2018 Mar 2. PMID: 29500187
  • Getz KR, Adedokun B, Xu S, Toriola AT. Breastfeeding and Mammographic Breast Density: A Cross-sectional Study. Cancer prevention research (Philadelphia, Pa.). 2023 Jun 1;16(6):353-361. PMID: 36930943