Population Council Research that makes a difference

2011 International Conference on Family Planning
29 November–2 December 2011

Abstract

"Design and screening of new contraceptives for safety, efficacy, and additional health benefits"
Patricia Morris, Lyann Mitchell, Catherine Rapelje, John W. Townsend, KeumSil Hwang, and Régine Sitruk-Ware

Significance
Continued increases in the global incidence of breast cancer are alarming to people worldwide but perhaps even more so in developing countries where routine overall health care and, in particular, early breast cancer detection and treatments are still very limited. While the observed global increases in breast cancer incidence and risk are likely due to multiple contributory causes including genetics and environmental factors such as nutrition, exposure to chemical contaminants, changes in lifestyles and reproductive behavior, the availability to offer a new contraceptive for family planning with the additional benefit of supporting breast health would have the potential to increase client acceptability and encourage regular use.

Background
An important role in normal mammary development and function is played by molecules that are responsive to selective hormones such as progesterone receptors (PRs). Imbalances in PR regulation are thought to play a significant role in the development of breast cancers. Selective PR modulators (SPRMs) represent a class of molecules with poorly characterized effects on the growth and hormone responsiveness of the cells within human reproductive tissues. Thus, individual compounds with unique synthetic modifications within large chemical families such as the SPRMs remain underexplored for safe and effective contraceptive use or hormone therapy in women.

Hypothesis
We propose that new advances in state-of the-art profiling of gene and molecular expression offers an opportunity to identify new panels of precision biomarkers and breast tissue cell mechanisms for the R&D screening and prioritization of new, safe and effective contraceptives. Our objective is to develop and validate rigorous prognostic and predictive reproductive tissue biomarkers for the optimal selection of lead contraceptive compounds and strategies for clinical development.

Objective
Our overarching aim is to select key mechanistically important biomarkers for screening and to better characterize the mechanisms and safety of SPRMs or other new drug candidates for potential dual health benefits, i.e., safe contraception and breast protection.

Methods
Experiments were conducted using live normal and cancer human breast cells exposed to either short (0–72 hours) or long-term (1–7 months) contraceptive treatments. Changes in expression of genes or specific proteins were assessed using cutting-edge technology in our laboratory.

Results/Key Findings
We determined that short- and long-term Ulipristal acetate (UPA) treatment safely and significantly slows breast epithelial cell cycle cell progression, increases cells in a resting or quiescent stage (G0/G1) and reduces growth of both normal slow-proliferating or faster growing tumor generating cancer cells. For breast cells treated with a specific type of growth factor (5-to-30 min.), our data show that UPA significantly decreases the activated state of a pro-growth receptor and its growth factor-activation in breast cancer cells compared to their matched controls. These findings are suggestive that in the presence of abnormally high local amounts of growth factors or their receptors, as proposed to occur early during some pre-tumor stage emergence of cells, the UPA exposed cells do not react with increases in proliferation. Using statistical analyses and high stringency characteristics, additional top candidate genes and biomarkers involved in cell cycle and overall protective changes have been identified. With the identification of these candidate biomarkers, we have developed and validated a new high-throughput screening assay applicable for contraceptive development.

Knowledge Contribution/Conclusion
Taken together, our data are consistent with human breast safety during long-term use of this particular SPRM and the findings suggest potential protection against abnormal growth as a breast health benefit. In addition, new reproductive tissue biomarkers for screening of contraceptives for both women and men have been identified.

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Offsite link: 2011 International Family Planning conference Web site

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Diane Rubino: drubino@popcouncil.org; +1 212 339 0617