Abstract
Breast cancer is a leading cause of cancer death in women, with the majority of these deaths caused by metastasis to distant organs. The most common site of breast cancer metastasis is the bone, which has been shown to provide a rich microenvironment that supports the migration and growth of breast cancer cells. Additionally, growing evidence suggests that breast cancer cells that do successfully metastasize have a stem-like phenotype including high activity of aldehyde dehydrogenase (ALDH) and/or a CD44+CD24- phenotype. In the current study, we tested the hypothesis that these ALDHhiCD44+CD24- breast cancer cells interact with factors in the bone secondary organ microenvironment to facilitate metastasis. Specifically, we focused on bone-derived osteopontin and its ability to promote the migration and stem-like phenotype of breast cancer cells. Our results indicate that bone-derived osteopontin promotes the migration, tumorsphere-forming ability and colony-forming ability of whole population and ALDHhiCD44+CD24- breast cancer cells in bone marrow-conditioned media (an ex vivo representation of the bone microenvironment) (p≤0.05). We also demonstrate that CD44 and RGD-dependent cell surface integrins facilitate this functional response to bone-derived osteopontin (p≤0.05), potentially through activation of WNK-1 and PRAS40-related pathways. Our findings suggest that soluble bone-derived osteopontin enhances the ability of breast cancer cells to migrate to the bone and maintain a stem-like phenotype within the bone microenvironment, and this may contribute to the establishment and growth of bone metastases.
Highlights
Breast cancer is the most frequently diagnosed cancer among North American women, currently accounting for approximately 26% of all newly diagnosed cancer cases [1, 2]
Of the proteins identified in Bone marrow-conditioned media (BMCM), several were found to be associated with metastasis, including the soluble phosphoprotein osteopontin (OPN) (S1 Table)
TranswellTM migration assays were used to assess the migration of MDA-MB-231 and SUM-159 human breast cancer cells to basal media, BMCM and BMCM depleted of OPN
Summary
Breast cancer is the most frequently diagnosed cancer among North American women, currently accounting for approximately 26% of all newly diagnosed cancer cases [1, 2]. Breast cancer’s high mortality rate (ranked second among women after lung cancer) is primarily due to the failure of conventional therapy to mitigate and eliminate metastatic disease. Bone-derived OPN promotes migration and stem-like behavior of breast cancer cells. Master’s program (to M.M.P), the Canadian Institutes of Health Research (CIHR)–Strategic Training Program (to M.M.P., G.M.P and J.E.C.) and the Pamela Greenaway-Kohlmeier Translational Breast Cancer Research Unit at the London Regional Cancer Program The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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