High hopes for RANKL: will the mouse model live up to its promise?

Cathrin Brisken, Tamara Tanos
BioMed Central, 2011
Article

Résumé

The steroid hormones, estrogens and progesterone are key drivers of postnatal breast development and are linked to breast carcinogenesis. Experiments in the mouse mammary gland have revealed that they rely on paracrine factors to relegate their signal locally and to amplify it. In particular, RANKL is a key mediator of progesterone action. Systemic inhibition of RANKL blocked proliferation in the mammary epithelium with potential clinical implications: a RANKL-inhibiting antibody, Denosumab (Amgen), has been approved by the US Food and Drug Administration for osteoporosis treatment. Two publications now provide evidence that progestin-driven mouse mammary tumorigenesis can be blocked by ablating RANK signaling. Can the osteoporosis drug help breast cancer patients? The burning question now is whether the role of this pathway is conserved in the human breast and whether RANKL signaling has a role in the pathogenesis of one or more subtypes of breast cancer.

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https://infoscience.epfl.ch/record/163580?ln=fr

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Progesterone/RANKL Is a Major Regulatory Axis in the Human Breast

Ayyakkannu Ayyanan, Cathrin Brisken, Maryse Fiche, Maria Gutierrez Najera, Georgios Sflomos, Tamara Tanos

Estrogens and progesterones are major drivers of breast development but also promote carcinogenesis in this organ. Yet, their respective roles and the mechanisms underlying their action in the human breast are unclear. Receptor activator of nuclear factor kappa B ligand (RANKL) has been identified as a pivotal paracrine mediator of progesterone function in mouse mammary gland development and mammary carcinogenesis. Whether the factor has the same role in humans is of clinical interest because an inhibitor for RANKL, denosumab, is already used for the treatment of bone disease and might benefit breast cancer patients. We show that progesterone receptor (PR) signaling failed to induce RANKL in PR+ breast cancer cell lines and in dissociated, cultured breast epithelial cells. In clinical specimens from healthy donors and intact breast tissue microstructures, hormone response was maintained and RANKL expression was under progesterone control, which increased RNA stability. RANKL was sufficient to trigger cell proliferation and was required for progesterone-induced proliferation. The findings were validated in vivo where RANKL protein expression in the breast epithelium correlated with serum progesterone levels and the protein was expressed in a subset of luminal cells that express PR. Thus, important hormonal control mechanisms are conserved across species, making RANKL a potential target in breast cancer treatment and prevention.

American Association for the Advancement of Science2013

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Progesterone signalling in breast cancer: a neglected hormone coming into the limelight

Cathrin Brisken

Abstract | Understanding the biology of the breast and how ovarian hormones impinge on it is key to rational new approaches in breast cancer prevention and therapy. Because of the success of selective oestrogen receptor modulators (SERMs), such as tamoxifen, and aromatase inhibitors in breast cancer treatment, oestrogens have long received the most attention. Early progesterone receptor (PR) antagonists, however, were dismissed because of severe side effects, but awareness is now increasing that progesterone is an important hormone in breast cancer. Oestrogen receptor-α (ERα) signalling and PR signalling have distinct roles in normal mammary gland biology in mice; both ERα and PR delegate many of their biological functions to distinct paracrine mediators. If the findings in the mouse model translate to humans, new preventive and therapeutic perspectives might open up.

Nature Publishing Group2013

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Progesterone is considered as the pregnancy hormone and acts on many different target tissues. Progesterone receptor (PR) signaling is important for normal development and the physiologic function of the breast and impinges on breast carcinogenesis. Both systemically and locally, in the breast epithelium, there are multiple layers of complexity to progesterone action, many of which have been revealed through experiments in mice. The hormone acts via its receptor expressed in a subset of cells, the sensor cells, in the breast epithelium with different signaling outcomes in individual cells eliciting distinct cell-intrinsic and paracrine signaling involving different mediators for different intercellular interactions. PR expression itself is developmentally regulated and the biological outcome of PR signaling depends on the developmental stage of the mammary gland and the endocrine context. During both puberty and adulthood PR activates stem and progenitor cells through Wnt4-driven activation of the myoepithelium with downstream Adamts18-induced changes in extracellualr matrix (ECM) / basal membrane (BM). During estrous cycling and pregnancy, the hormone drives a major cell expansion through Rankl. At all stages, PR signaling is closely tied to estrogen receptor a (ER) signaling. As the PR itself is a target gene of ER, the complex interactions are experimentally difficult to dissect and still poorly understood. Ex vivo models of the human breast and studies on biopsy samples show that major signaling axes are conserved across species. New intraductal xenograft models hold promise to provide a better understanding of PR signaling in the normal breast epithelium and in breast cancer development in the near future.

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