ABCC5 supports osteoclast formation and promotes breast cancer metastasis to bone
1 Department of Medicine, McGill University, 1110 Pine Avenue West, Montreal, Quebec, H3A 1A3, Canada
2 Faculty of Dentistry, McGill University, 3640 University Street, Montreal, Quebec, H3A 0C7, Canada
3 Shriners Hospital for Children, 1529 Cedar Avenue, Montreal, Quebec, H3G 1A6, Canada
4 Centre for Bioinformatics, McGill University, 3649 Promenade Sir William Osler, Montreal, Quebec, H3G 0B1, Canada
5 Department of Pathology, McGill University, 3775 University Street, Montreal, Quebec, H3A 2B4, Canada
6 Breast Cancer Functional Genomics Group, McGill University, 1160 Pine Avenue West, Montreal, Quebec, H3A 1A3, Canada
7 Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, Quebec, H3G 1Y6, Canada
8 Department of Anatomy and Cell Biology, McGill University, 3640 University Street, Montreal, Quebec, H3A 2B2, Canada
9 Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue West, Montreal, Quebec, H3A 1A3, Canada
10 Division of Medical Oncology, Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario, M5T 2M9, Canada
11 Division of Medical Oncology, Ottawa Hospital Cancer Centre, 501 Smyth Road, Ottawa, Ontario, K1H 8L6, Canada
12 VU Medical Center, Department of Pathology, Postbus 7057 1007 MB, Amsterdam, The Netherlands
Breast Cancer Research 2012, 14:R149 doi:10.1186/bcr3361Published: 22 November 2012
Bone is the most common site of breast cancer metastasis, and complications associated with bone metastases can lead to a significantly decreased patient quality of life. Thus, it is essential to gain a better understanding of the molecular mechanisms that underlie the emergence and growth of breast cancer skeletal metastases.
To search for novel molecular mediators that influence breast cancer bone metastasis, we generated gene-expression profiles from laser-capture microdissected trephine biopsies of both breast cancer bone metastases and independent primary breast tumors that metastasized to bone. Bioinformatics analysis identified genes that are differentially expressed in breast cancer bone metastases compared with primary, bone-metastatic breast tumors.
ABCC5, an ATP-dependent transporter, was found to be overexpressed in breast cancer osseous metastases relative to primary breast tumors. In addition, ABCC5 was significantly upregulated in human and mouse breast cancer cell lines with high bone-metastatic potential. Stable knockdown of ABCC5 substantially reduced bone metastatic burden and osteolytic bone destruction in mice. The decrease in osteolysis was further associated with diminished osteoclast numbers in vivo. Finally, conditioned media from breast cancer cells with reduced ABCC5 expression failed to induce in vitro osteoclastogenesis to the same extent as conditioned media from breast cancer cells expressing ABCC5.
Our data suggest that ABCC5 functions as a mediator of breast cancer skeletal metastasis. ABCC5 expression in breast cancer cells is important for efficient osteoclast-mediated bone resorption. Hence, ABCC5 may be a potential therapeutic target for breast cancer bone metastasis.