Expression and Circulating Levels of Perlecan in Breast Cancer - Implications for Oestrogen Dependent Stromal Remodeling

Abstract

Localised breast cancer can be cured by surgery and adjuvant treatments, but mortality remains high as some tumours metastasize early. Perlecan is a basement membrane (BM) protein involved in tumour development and progression. Here, mRNA and protein expression of perlecan, and mRNA expression of matrix degrading enzymes were studied in normal breast and invasive breast cancer, and correlated to prognostic risk factors, in particular oestrogen status. Moreover, plasma levels of perlecan were measured in patients with breast cancer and compared with controls. mRNA data was extracted from the Cancer Genome Atlas database. Perlecan protein expression was visualized using immunofluorescence and plasma levels measured by ELISA assay. Perlecan mRNA levels were twice as high in normal breast compared with breast cancer tissue. A strong correlation was found between mRNA expression of perlecan and several matrix-degrading enzymes in oestrogen receptor positive (ER+) tumours. Perlecan protein was localized to both epithelial and vascular BMs, but absent in the stroma in normal breast. In breast cancer, the expression of perlecan in epithelial BM was fragmented or completely lost, with a marked upregulation of perlecan expression in the stroma. Significantly higher levels of perlecan were found in plasma of ER+ patients when compared with ER-patients. This study shows that perlecan expression and degradation in breast cancer may be linked to the ER status of the tumour.

Novel Insight Into Glycosaminoglycan Biosynthesis Based on Gene Expression Profiles

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Proteoglycans in the Pathogenesis of Hormone-Dependent Cancers: Mediators and Effectors

“…PGs are discretely expressed in normal breast tissue depending on hormone status, whereas there are significant alterations of PGs in BC tissues. One example is the pericellular PG perlecan, whose expression is significantly attenuated in BC compared with in healthy tissue [ 72 ]. These changes in mammographic density, dependent on PGs, are attributed to their ability to retain water [ 73 ].…”

Collagen XVIII promotes breast cancer through EGFR/ErbB signaling and its ablation improves the efficacy of ErbB-targeting inhibitors

“…Our recent analysis has shown that the expression of a variety of ECM components in cancers is precisely regulated by specific oncogenic drivers and downstream transcription factors and correlates with the patient’s prognosis (16) . This study and a number of others, including our recent works (17–19) , highlight the utility of ECM molecules as diagnostic biomarkers and in disease follow-up and unveil new therapeutic possibilities for inhibiting cancer progression and metastasis and dismantling resistance to cancer therapies by targeting the ECM (12–15) .…”