Anti-progestin therapy targets hallmarks of breast cancer risk – Nature

Report on a Therapeutic Cancer Prevention Trial in the Context of Sustainable Development Goals

Introduction: Aligning Breast Cancer Prevention with Global Goals

Breast cancer represents a significant global health challenge, directly impeding progress towards several United Nations Sustainable Development Goals (SDGs). As the leading cause of cancer-related mortality in women, it poses a direct threat to SDG 3: Good Health and Well-being, particularly Target 3.4, which aims to reduce premature mortality from non-communicable diseases. Furthermore, its disproportionate impact on women undermines SDG 5: Gender Equality by affecting female health, economic participation, and overall well-being. This report details the findings of the Breast Cancer-Anti-Progestin Prevention Study 1 (BC-APPS1), an innovative clinical trial that explores a preventative strategy with the potential to advance these critical global goals.

Study Overview and Contribution to SDG 3 (Good Health and Well-being)

Research Objective and Methodology

The BC-APPS1 trial was designed to assess the efficacy of progesterone receptor antagonism in reducing surrogate markers of breast cancer risk, thereby contributing to preventative healthcare and the reduction of non-communicable disease burdens as outlined in SDG 3. The study’s framework and key parameters are outlined below:

• Objective: To determine if a 12-week course of ulipristal acetate, a progesterone receptor antagonist, could reduce biological and clinical markers of breast cancer risk.
• Participants: The study involved 24 premenopausal women with an increased familial risk of developing breast cancer.
• Innovative Approach (SDG 9): In line with SDG 9: Industry, Innovation, and Infrastructure, the trial employed advanced scientific methodologies, including multi-layered OMICs analyses, live-cell approaches, single-cell RNA sequencing, and atomic force microscopy to generate comprehensive biological data.

Primary Outcomes and Impact on NCD Prevention (Target 3.4)

The trial successfully demonstrated that progesterone receptor antagonism significantly reduces key risk markers, offering a promising avenue for primary cancer prevention. These outcomes directly support the aims of SDG 3 by providing a potential therapeutic intervention to lower disease incidence.

1. Reduced Cellular Proliferation: Treatment with ulipristal acetate led to a significant reduction in epithelial proliferation (Ki67), a key indicator of cellular activity that can precede malignancy.
2. Suppression of Cancer-Precursor Cells: The study observed a marked decrease in the proportion, proliferation, and colony-forming capacity of luminal progenitor cells, which are the putative cell of origin for aggressive breast cancers. Targeting these precursor cells is a fundamental step in cancer prevention.
3. Reduction in Clinical Risk Markers: Clinical imaging via MRI confirmed a reduction in fibroglandular volume, a surrogate for mammographic density, which is one of the strongest known risk factors for breast cancer.

Cellular and Molecular Mechanisms: A Deeper Dive into Health Innovation (SDG 9)

Extracellular Matrix Remodeling

The study’s multi-omic approach provided unprecedented insight into the molecular changes induced by the therapy, revealing that its preventative effects extend beyond epithelial cells to the surrounding microenvironment. This contributes to the body of scientific knowledge, a key component of enhancing scientific research under SDG 9.

• Single-cell RNA sequencing, proteomics, and histology identified extensive remodeling of the extracellular matrix (ECM).
• A significant reduction in collagen organization and overall tissue stiffness was observed post-treatment.
• Collagen VI was identified as the most significantly downregulated protein, highlighting its potential role as a therapeutic target and biomarker.

Linking Stromal Changes to Progenitor Cell Activity

A novel mechanistic link was established between the stromal microenvironment and the activity of cancer-precursor cells, strengthening the biological rationale for this preventative strategy.

• An unanticipated spatial association was discovered between high collagen VI levels and the localization of SOX9^high luminal progenitor cells.
• Functional experiments confirmed that culturing primary human breast epithelial cells in a stiff, collagen-rich environment increased luminal progenitor activity.
• This stiffness-induced activity was effectively antagonized by anti-progestin therapy, demonstrating that the treatment disrupts a critical feedback loop between the stroma and epithelial cells that promotes a high-risk state.

Broader Implications for Sustainable Development

Advancing Gender Equality and Reducing Inequalities (SDG 5 & SDG 10)

By focusing on a disease that primarily affects women, this research is intrinsically linked to SDG 5: Gender Equality. An effective preventative strategy would empower women by protecting their health and ensuring their continued participation in economic and social life. Furthermore, by developing therapeutic prevention that could be more accessible than complex treatments, this work has the long-term potential to contribute to SDG 10: Reduced Inequalities, by mitigating health disparities in breast cancer outcomes across different populations.

Economic and Societal Benefits (SDG 8)

Preventing breast cancer aligns with SDG 8: Decent Work and Economic Growth. Reducing the incidence of this disease lessens the economic burden on healthcare systems, minimizes productivity losses, and supports a healthier workforce, which is essential for sustained and inclusive economic growth.

Conclusion and Future Directions

The BC-APPS1 trial provides compelling evidence that anti-progestin therapy can modify key hallmarks of breast cancer risk by suppressing cancer-precursor cells and remodeling the tissue microenvironment. The findings offer a biologically informed template for future cancer prevention trials and highlight the potential of progesterone receptor antagonists as a viable strategy for premenopausal women at high risk.

This research represents a significant step towards achieving SDG 3 by addressing a major non-communicable disease through prevention. Its focus on a women’s health issue also supports SDG 5, while its innovative methodology aligns with SDG 9. Future long-term studies are necessary to confirm these findings and evaluate safety, but this work demonstrates a clear pathway for translating advanced biological understanding into clinical interventions that support global health and sustainable development.

Analysis of Sustainable Development Goals in the Article

1. Which SDGs are addressed or connected to the issues highlighted in the article?

1. SDG 3: Good Health and Well-being

   • Explanation: The article is fundamentally centered on health. It addresses breast cancer, which it identifies as “the leading cause of cancer-related death in women worldwide” and “the leading cause of cancer-related mortality in women globally.” The entire study is a therapeutic cancer prevention trial aimed at reducing the risk of this major health issue, directly contributing to the overarching goal of ensuring healthy lives and promoting well-being for all at all ages.

2. What specific targets under those SDGs can be identified based on the article’s content?

1. Target 3.4: By 2030, reduce by one third premature mortality from non-communicable diseases through prevention and treatment and promote mental health and well-being.

   • Explanation: Breast cancer is a non-communicable disease (NCD). The article’s core focus is on a prevention study (“Breast Cancer-Anti-Progestin Prevention Study 1”) that assesses whether a specific therapy can reduce “surrogate markers of breast cancer risk.” By investigating methods to prevent the onset of aggressive breast cancers, the research directly addresses the “prevention and treatment” aspect of this target, with the ultimate goal of reducing premature mortality from this disease.

2. Target 3.d: Strengthen the capacity of all countries, in particular developing countries, for early warning, risk reduction and management of national and global health risks.

   • Explanation: The study identifies and validates “clinically relevant surrogate indicators of risk reduction,” such as mammographic density and various molecular markers. This research contributes to the global scientific knowledge base for breast cancer risk reduction. By establishing a “template for biologically informed early-phase therapeutic cancer prevention trials,” it strengthens the capacity for managing a global health risk, providing insights that can be adapted and applied worldwide.

3. Are there any indicators mentioned or implied in the article that can be used to measure progress towards the identified targets?

1. Official SDG Indicators

   • Indicator 3.4.1: Mortality rate attributed to cardiovascular disease, cancer, diabetes or chronic respiratory disease.
     • Explanation: The article establishes the relevance of this indicator by stating that “Breast cancer is the leading cause of cancer-related mortality in women globally.” While the study itself does not measure mortality rates, its entire premise is to find preventive measures that would ultimately contribute to lowering this specific mortality rate.

2. Implied/Study-Specific Indicators

   • Epithelial proliferation (Ki67 levels): The article explicitly states this was the “primary end point of the BC-APPS1 study.” The finding of a “significant reduction in proliferation” serves as a direct, measurable indicator of the therapeutic intervention’s biological effect on cancer risk.
   • Proportion and activity of luminal progenitor cells: The study measured a “significant reduction in the luminal progenitor… fraction” and reduced “colony formation capacity.” Since these cells are the “putative cell of origin of aggressive breast cancers,” their reduction is a key molecular indicator of decreased cancer risk.
   • Fibroglandular volume (FGV) / Mammographic density: The article notes a “significant reduction in FGV (a surrogate for mammographic density)” measured by MRI. As mammographic density is “one of the strongest risk factors for breast cancer,” its reduction is a critical clinical indicator of progress in risk prevention.
   • Tissue stiffness and collagen organization: The study used atomic force microscopy and histology to identify “reduced collagen organization and tissue stiffness.” These are biomechanical and structural indicators that correlate with a lower-risk breast tissue microenvironment.

4. Summary Table of SDGs, Targets, and Indicators

Source: nature.com