Abstract
Bone metastasis remains a major cause of mortality and morbidity in breast cancer. Therefore, there is an urgent need to better select high-risk patients in order to adapt patient’s treatment and prevent bone recurrence. Here, we found that integrin alpha5 (ITGA5) was highly expressed in bone metastases, compared to lung, liver, or brain metastases. High ITGA5 expression in primary tumors correlated with the presence of disseminated tumor cells in bone marrow aspirates from early stage breast cancer patients (n = 268; p = 0.039). ITGA5 was also predictive of poor bone metastasis-free survival in two separate clinical data sets (n = 855, HR = 1.36, p = 0.018 and n = 427, HR = 1.62, p = 0.024). This prognostic value remained significant in multivariate analysis (p = 0.028). Experimentally, ITGA5 silencing impaired tumor cell adhesion to fibronectin, migration, and survival. ITGA5 silencing also reduced tumor cell colonization of the bone marrow and formation of osteolytic lesions in vivo. Conversely, ITGA5 overexpression promoted bone metastasis. Pharmacological inhibition of ITGA5 with humanized monoclonal antibody M200 (volociximab) recapitulated inhibitory effects of ITGA5 silencing on tumor cell functions in vitro and tumor cell colonization of the bone marrow in vivo. M200 also markedly reduced tumor outgrowth in experimental models of bone metastasis or tumorigenesis, and blunted cancer-associated bone destruction. ITGA5 was not only expressed by tumor cells but also osteoclasts. In this respect, M200 decreased human osteoclast-mediated bone resorption in vitro. Overall, this study identifies ITGA5 as a mediator of breast-to-bone metastasis and raises the possibility that volociximab/M200 could be repurposed for the treatment of ITGA5-positive breast cancer patients with bone metastases.
Highlights
Supplementary information The online version of this article contains supplementary material, which is available to authorized users.Pharmacogénomique, Paris, FranceBreast cancer can be successfully treated when the disease is detected early, but the patient survival markedly decreases once metastatic spread occurs [1]
The analysis of 855 radically resected primary breast tumors with known location of the first distant metastasis led to 146 genes that were significantly upregulated in primary tumors from patients who first relapsed in bone, compared to patients who first relapsed at non-bone metastatic sites or did not relapse after 200 months follow-up (Fig. 1B and Table S1)
Eight genes were common to gene sets #1 and #2: EGFcontaining fibulin-like extracellular matrix protein 2 (EFEMP2), integrin alpha5 (ITGA5), KIAA1199, microfibrillar-associated protein 5 (MFAP5), plexin domain-containing protein 1 (PLXDC1), SPARC (Osteonectin), Cwcv and kazal-like domains proteoglycan 1 (SPOCK1), T-cell immune regulator 1 (TCIRG1), and transforming growth factor beta1-induced transcript 1 (TGFB1I1) (Fig. 1C)
Summary
Breast cancer can be successfully treated when the disease is detected early, but the patient survival markedly decreases once metastatic spread occurs [1]. In this respect, the prognosis for patients with bone metastasis is generally poor Sheffield, UK. Several studies have underlined that tumor cell dissemination to the bone marrow is an early metastasis event and represents an independent prognostic factor for poor clinical outcome [3,4,5]. Molecular mechanisms regulating bone homing and colonization by breast cancer cells remain, still poorly understood
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