Laminin N-terminus α31 is upregulated in invasive ductal breast cancer and changes the mode of tumour invasion

Abstract

Laminin N-terminus α31 (LaNt α31) is an alternative splice isoform derived from the laminin α3 gene. The LaNt α31 protein is enriched around the terminal duct lobular units in normal breast tissue. In the skin and cornea the protein influences epithelial cell migration and tissue remodelling. However, LaNt α31 has never been investigated in a tumour environment. Here we analysed LaNt α31 in invasive ductal carcinoma and determined its contribution to breast carcinoma invasion. LaNt α31 expression and distribution were analysed by immunohistochemistry in human breast tissue biopsy sections and tissue microarrays covering 232 breast cancer samples. This analysis revealed LaNt α31 to be upregulated in 56% of invasive ductal carcinoma specimens compared with matched normal tissue, and further increased in nodal metastasis compared with the tumour mass in 45% of samples. 65.8% of triple negative cases displayed medium to high LaNt α31 expression. To study LaNt α31 function, an adenoviral system was used to induce expression in MCF-7 and MDA-MB-231 cells. 2D cell migration and invasion into collagen hydrogels were not significantly different between LaNt α31 overexpressing cells and control treated cells. However, LaNt α31 overexpression reduced the proliferation rate of MCF-7 and MDA-MB-231 cells. Moreover, LaNt α31 overexpressing MDA-MB-231 cells displayed a striking change in their mode of invasion into laminin-containing Matrigel; changing from multicellular streaming to individual cellular-invasion. In agreement with these results, 66.7% of the tumours with the highest LaNt α31 expression were non-cohesive. Together these findings indicate that breast cancer-associated changes in LaNt α31 expression could contribute to the processes involved in tumour invasion and may represent a new therapeutic target.

Heterogeneity and versatility of the extracellular matrix during the transition from pleomorphic adenoma to carcinoma ex pleomorphic adenoma: cumulative findings from basic research and new insights

“…In tumorigenesis, once activated, these proteins promote cell proliferation, migration, differentiation, and metastasis ( 98 , 99 ). Indeed, laminin facilitates cell migration and invasion in invasive ductal breast cancer ( 103 ), gastric cancer ( 104 ), and bladder cancer ( 105 ). In addition, laminin may be correlated with the immune response in ovarian cancer ( 104 ).…”

Laminin N‐terminus α31 expression during development is lethal and causes widespread tissue‐specific defects in a transgenic mouse model

“…37 Increased expression is associated with breast ductal carcinoma and in vitro overexpression leads to a change in the mode of breast cancer cell invasion through LM-rich matrices. 38 LaNt α31 is also transiently upregulated during re-epithelialization of ex vivo corneal burn wounds and in limbal stem cell activation assays. 36 In epidermal and corneal keratinocytes, knockdown or overexpression experiments revealed that modulating LaNt α31 levels leads to reduced migration rates and changes to cell-to-matrix adhesion.…”

“…LaNt α31 is expressed in the basal layer of epithelia in the skin, 24 cornea 36 and digestive tract, the ECM around terminal duct lobular units of the breast and alveolar air sacs in the lung, and is widely expressed by endothelial cells 37 . Increased expression is associated with breast ductal carcinoma and in vitro overexpression leads to a change in the mode of breast cancer cell invasion through LM‐rich matrices 38 . LaNt α31 is also transiently upregulated during re‐epithelialization of ex vivo corneal burn wounds and in limbal stem cell activation assays 36 .…”