Biphasic α2β1 Integrin Expression in Breast Cancer Metastasis to Bone.

Milene N O Moritz,Alyssa R Merkel,Ean G Feldman,Heloisa S Selistre-De-Araujo,Julie A Rhoades Sterling

doi:10.3390/ijms22136906

Abstract

Integrins participate in the pathogenesis and progression of tumors at many stages during the metastatic cascade. However, current evidence for the role of integrins in breast cancer progression is contradictory and seems to be dependent on tumor stage, differentiation status, and microenvironmental influences. While some studies suggest that loss of α2β1 enhances cancer metastasis, other studies suggest that this integrin is pro-tumorigenic. However, few studies have looked at α2β1 in the context of bone metastasis. In this study, we aimed to understand the role of α2β1 integrin in breast cancer metastasis to bone. To address this, we utilized in vivo models of breast cancer metastasis to bone using MDA-MB-231 cells transfected with an α2 expression plasmid (MDA-OEα2). MDA cells overexpressing the α2 integrin subunit had increased primary tumor growth and dissemination to bone but had no change in tumor establishment and bone destruction. Further in vitro analysis revealed that tumors in the bone have decreased α2β1 expression and increased osteolytic signaling compared to primary tumors. Taken together, these data suggest an inverse correlation between α2β1 expression and bone-metastatic potential. Inhibiting α2β1 expression may be beneficial to limit the expansion of primary tumors but could be harmful once tumors have established in bone.

Highlights

Breast cancer is the most common cancer among women and the second leading cause of cancer-related deaths [1]
We demonstrate that α2β1 integrin promotes tumor development at the primary site and metastasis to bone but has no effect on bone destruction once tumors have established in bone
Considering the data presented in this study, we suggest that α2β1 integrin expression may be involved in the oncogenic switch of primary tumors to a migratory and metastatic phenotype, while inactivation of α2β1 by bone microenvironmental influences, such as transformation growth factor β (TGF-β) and mechanical force, promote tumor-induced bone disease

Summary

Introduction

Breast cancer is the most common cancer among women and the second leading cause of cancer-related deaths [1]. Despite advances in early detection and therapeutic options for patients, metastatic disease remains the leading cause of patient mortality. Metastatic breast cancer cells have a high preference for bone. Despite the high prevalence of bone metastases, the pathology and risk factors of breast cancer metastasis to bone are not fully understood. Recent studies have revealed that the expression profile of primary tumors and composition of the surrounding extracellular matrix (ECM) are important factors contributing to tumor progression and metastasis [5,6,7]. Integrins are αβ heterodimeric transmembrane receptors that support cell adhesion to the extracellular matrix (ECM) and trigger intracellular signaling that can modify cellular behavior [11,12]

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