RANKL/RANK/OPG system beyond bone remodeling: involvement in breast cancer and clinical perspectives
Abstract RANKL/RANK/OPG system consists of three essential signaling molecules: i) the receptor activator of nuclear factor (NF)-kB-ligand (RANKL), ii) the receptor activator of NF-kB (RANK), and iii) the soluble decoy receptor osteoprotegerin (OPG). Although this system is critical for the regulati...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-01-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13046-018-1001-2 |
| _version_ | 1828850081861730304 |
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| author | Marco Infante Alessandra Fabi Francesco Cognetti Stefania Gorini Massimiliano Caprio Andrea Fabbri |
| author_facet | Marco Infante Alessandra Fabi Francesco Cognetti Stefania Gorini Massimiliano Caprio Andrea Fabbri |
| author_sort | Marco Infante |
| collection | DOAJ |
| description | Abstract RANKL/RANK/OPG system consists of three essential signaling molecules: i) the receptor activator of nuclear factor (NF)-kB-ligand (RANKL), ii) the receptor activator of NF-kB (RANK), and iii) the soluble decoy receptor osteoprotegerin (OPG). Although this system is critical for the regulation of osteoclast differentiation/activation and calcium release from the skeleton, different studies have elucidated its specific role in mammary gland physiology and hormone-driven epithelial proliferation during pregnancy. Of note, several data suggest that progesterone induces mammary RANKL expression in mice and humans. In turn, RANKL controls cell proliferation in breast epithelium under physiological conditions typically associated with higher serum progesterone levels, such as luteal phase of the menstrual cycle and pregnancy. Hence, RANKL/RANK system can be regarded as a major downstream mediator of progesterone-driven mammary epithelial cells proliferation, potentially contributing to breast cancer initiation and progression. Expression of RANKL, RANK, and OPG has been detected in breast cancer cell lines and in human primary breast cancers. To date, dysregulation of RANKL/RANK/OPG system at the skeletal level has been widely documented in the context of metastatic bone disease. In fact, RANKL inhibition through the RANKL-blocking human monoclonal antibody denosumab represents a well-established therapeutic option to prevent skeletal-related events in metastatic bone disease and adjuvant therapy-induced bone loss in breast cancer. On the other hand, the exact role of OPG in breast tumorigenesis is still unclear. This review focuses on molecular mechanisms linking RANKL/RANK/OPG system to mammary tumorigenesis, highlighting pre-clinical and clinical evidence for the potential efficacy of RANKL inhibition as a prevention strategy and adjuvant therapy in breast cancer settings. |
| first_indexed | 2024-12-12T23:04:51Z |
| format | Article |
| id | doaj.art-ee0e82a5aa5d4205bb71894741ea6e60 |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-12-12T23:04:51Z |
| publishDate | 2019-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-ee0e82a5aa5d4205bb71894741ea6e602022-12-22T00:08:44ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662019-01-0138111810.1186/s13046-018-1001-2RANKL/RANK/OPG system beyond bone remodeling: involvement in breast cancer and clinical perspectivesMarco Infante0Alessandra Fabi1Francesco Cognetti2Stefania Gorini3Massimiliano Caprio4Andrea Fabbri5Unit of Endocrinology and Metabolic Diseases, Department of Systems Medicine, CTO A. Alesini Hospital, ASL Roma 2, University Tor VergataDivision of Medical Oncology 1, Regina Elena National Cancer InstituteDivision of Medical Oncology 1, Regina Elena National Cancer InstituteLaboratory of Cardiovascular Endocrinology, IRCCS San Raffaele PisanaLaboratory of Cardiovascular Endocrinology, IRCCS San Raffaele PisanaUnit of Endocrinology and Metabolic Diseases, Department of Systems Medicine, CTO A. Alesini Hospital, ASL Roma 2, University Tor VergataAbstract RANKL/RANK/OPG system consists of three essential signaling molecules: i) the receptor activator of nuclear factor (NF)-kB-ligand (RANKL), ii) the receptor activator of NF-kB (RANK), and iii) the soluble decoy receptor osteoprotegerin (OPG). Although this system is critical for the regulation of osteoclast differentiation/activation and calcium release from the skeleton, different studies have elucidated its specific role in mammary gland physiology and hormone-driven epithelial proliferation during pregnancy. Of note, several data suggest that progesterone induces mammary RANKL expression in mice and humans. In turn, RANKL controls cell proliferation in breast epithelium under physiological conditions typically associated with higher serum progesterone levels, such as luteal phase of the menstrual cycle and pregnancy. Hence, RANKL/RANK system can be regarded as a major downstream mediator of progesterone-driven mammary epithelial cells proliferation, potentially contributing to breast cancer initiation and progression. Expression of RANKL, RANK, and OPG has been detected in breast cancer cell lines and in human primary breast cancers. To date, dysregulation of RANKL/RANK/OPG system at the skeletal level has been widely documented in the context of metastatic bone disease. In fact, RANKL inhibition through the RANKL-blocking human monoclonal antibody denosumab represents a well-established therapeutic option to prevent skeletal-related events in metastatic bone disease and adjuvant therapy-induced bone loss in breast cancer. On the other hand, the exact role of OPG in breast tumorigenesis is still unclear. This review focuses on molecular mechanisms linking RANKL/RANK/OPG system to mammary tumorigenesis, highlighting pre-clinical and clinical evidence for the potential efficacy of RANKL inhibition as a prevention strategy and adjuvant therapy in breast cancer settings.http://link.springer.com/article/10.1186/s13046-018-1001-2RANKLRANKOPGMammary glandBreast tumorigenesisBreast cancer |
| spellingShingle | Marco Infante Alessandra Fabi Francesco Cognetti Stefania Gorini Massimiliano Caprio Andrea Fabbri RANKL/RANK/OPG system beyond bone remodeling: involvement in breast cancer and clinical perspectives Journal of Experimental & Clinical Cancer Research RANKL RANK OPG Mammary gland Breast tumorigenesis Breast cancer |
| title | RANKL/RANK/OPG system beyond bone remodeling: involvement in breast cancer and clinical perspectives |
| title_full | RANKL/RANK/OPG system beyond bone remodeling: involvement in breast cancer and clinical perspectives |
| title_fullStr | RANKL/RANK/OPG system beyond bone remodeling: involvement in breast cancer and clinical perspectives |
| title_full_unstemmed | RANKL/RANK/OPG system beyond bone remodeling: involvement in breast cancer and clinical perspectives |
| title_short | RANKL/RANK/OPG system beyond bone remodeling: involvement in breast cancer and clinical perspectives |
| title_sort | rankl rank opg system beyond bone remodeling involvement in breast cancer and clinical perspectives |
| topic | RANKL RANK OPG Mammary gland Breast tumorigenesis Breast cancer |
| url | http://link.springer.com/article/10.1186/s13046-018-1001-2 |
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