In the Spotlight

Reproductive Sciences 20(7) 729 ª The Author(s) 2013 In the Spotlight Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1933719113491541 rs.sagepub.com Maria Rosa Maduro, PhD

A Functional Artificial A Potential New Target to Fight Breast The loss of ovarian function through either menopause, surgi- Cancer cal resection, or ablative therapy and its inherent cessation of Breast cancer is a leading cause of women mortality world- sex steroids’ production not only impairs a woman’s reproduc- wide. Although estrogen and progesterone are essential for tive ability but also leads to various pathological conditions breast development and function, they are also known to be ranging from urogenital complications to osteoporosis. Thus, deeply involved in breast cancer growth through mechanisms a cell/tissue delivery-based therapy that would that are still poorly understood in vivo. provide serum levels of close to the physiological Genetic studies have provided evidence that receptor activa- values would certainly be appealing for the treatment of tor of nuclear factor kB ligand (RANKL), a member of the ovarian hormone deprivation. tumor necrosis factor family, acts as an important paracrine Appropriately, Sittadjodi et al have recently published in the mediator of progesterone-induced proliferation in the adult journal Biomaterials (Biomaterials. 2013;34(10):2412-2420) mouse mammary gland, both in normal mammary develop- their ability to design a functional tissue-engineered endocrine ment and in mammary carcinogenesis. ovary that may be used for a cell/tissue delivery-based hor- Since systemic inhibition of RANKL in the mouse-blocked mone replacement therapy. progesterone-induced proliferation of the mammary epithe- Sittadjodi and colleagues used granulosa and theca cells lium, Tanos and colleagues became interested in understanding from of 21-day-old rats and encapsulated them in RANKL’s role in humans to determine its suitability as a drug multilayer alginate microcapsules to recapitulate the native target for breast cancer treatment. Their findings have recently follicular structure. The endocrine function of the multilayer- been published in the journal Science Translational Medicine encapsulated cells was assessed in vitro for a period of 30 days (Sci Transl Med. 2013;5(182):1-10). and compared to other schemes of encapsulation that were used Tanos et al developed an ex vivo model using breast tissue as controls to assess the importance of the multilayer structure. microstructures isolated from fresh clinical specimens that pre- The authors observed that all encapsulated cells showed serve extensive intercellular contacts and contain multiple cell sustained viability during long-term in vitro culture. However, types that allowed them to conclude that also in humans those cells assembled into a multilayer pattern were able to progesterone induces cell proliferation using RANKL as an secrete significantly higher and sustained concentrations of essential mediator. The authors observed that RANKL alone 17 b- than the other encapsulated cells in response to was sufficient to trigger cell proliferation in the mammary follicle-stimulating hormone and luteinizing hormone. epithelium as well as it was required for progesterone- Additionally, the cells in the multilayer capsules also secreted induced proliferation. in vitro, resembling an in vivo functional In addition, Tanos and colleagues verified that in vivo ovary. All these characteristics could not be mimicked when RANKL protein expression in the breast epithelium correlated the same cells were cultured in 2-dimensional over the same with serum progesterone levels and that the protein was 30-day period. expressed in a subset of luminal cells that express progesterone In sum, Sittadjodi and colleagues have been able to design a receptor. multilayer-engineered ovarian tissue capsule that responds to Thus, the findings by Tanos et al suggest that the pathways gonadotropins to secrete sex steroids and peptide hormones, that control mammary growth and development are largely recapitulating a native ovarian structure. Although these results conserved between the mouse and the human and that RANKL are exciting, further research is needed to confirm the function- signaling may provide a new and exciting target for breast ality and sustainability of this artificial ovary in vivo. cancer treatment and prevention.