Role of integrin α11β1 in breast cancer

Abstract

Breast cancer cells are strongly influenced by a complex tumor microenvironment comprised of a diversity of stromal cells, including a heterogeneous population of cancer associated fibroblasts (CAFs), in addition to the extracellular matrix and the interstitial fluid with its solutes. Integrins act as links between the extracellular matrix and the cell cytoskeleton, and integrin α11β1 had previously been shown to be important for fibroblast function in wound healing, fibrosis and in lung cancer. In this thesis, we aimed to achieve a better understanding of the expression and functions of integrin α11β1 in the breast tumor microenvironment.

In the first two papers we explored the effects of stromal integrin α11β1 in triple-negative breast cancer in integrin α11 knockout mice and demonstrated that integrin α11-deficiency reduced tumor interstitial fluid pressure and altered collagen fibril structure in MDA-MB-231 and MDA-MB-468 tumors. In addition, integrin α11-deficiency reduced MDA-MB-231 growth and the same trend was seen in MDA-MB-468 tumors. However, no effects of integrin α11β1 were seen in 4T1 tumors except altered collagen fibril structure. In the third paper, we validated new monoclonal antibodies against the human integrin α11 chain and established conditions for reproducible staining on formalin-fixed, paraffin-embedded (FFPE) human tissues. By investigating the expression of integrin α11 with the 210F4B6A4 monoclonal antibody in a large breast cancer cohort, we reported that integrin α11β1 is expressed in fibroblast-like, stromal cells in the vast majority of invasive breast carcinoma. Strong integrin α11β1 expression was associated with aggressive breast cancer features, although not with breast cancer specific survival. Further, integrin α11β1 co-localized with αSMA in fibroblast-like cells, and αSMA and cytokeratin 14 in a subset of breast myoepithelium.

In summary, this thesis has uncovered a new function of integrin α11β1 in the regulation of tumor interstitial fluid pressure in experimental breast cancer. Integrin α11β1 stimulated MDA-MB-231 growth in vivo and was associated with aggressive cancer phenotypes in human breast cancer, indicating that integrin α11β1 seems to be expressed in a pro-tumorigenic CAF subset. We also detected integrin α11β1 in a subset of breast myoepithelial cells, and the function in these cells is so far not known. Our new monoclonal antibodies against the integrin α11 chain represent new tools for use in further investigation of the expression and function of integrin α11β1.