Is the Mannose-6-Phosphate/Insulin-Like Growth Factor 2 Receptor Coded by a Breast Cancer Suppressor Gene?

Abstract

The multifunctional growth factor mannose-6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2-R) binds proteins sharing M6P signals, including cathepsins and IGF2. It is involved in targeting newly synthesized mannose-6-phosphorylated lysosomal enzymes, activating transforming growth factor beta (TGFbeta), and neutralising the mitogen IGF2 by transporting it to lysosomes. The M6P/IGF2-R was proposed as being coded by a tumor suppressor gene. We measured gene expression at the protein level by quantitative immunohistochemistry, using chicken high affinity IgY antibodies directed against human M6P/IGF2-R. Chicken immunization was performed with human purified M6P/IGF2-R, and IgY antibodies were extracted from egg yolk by polyethylene glycol precipitation method. The biosensor analysis showed that IgY antibodies bind M6P/IGF2-R with high affinity (Kd = 7.5 nM). Quantitative immunohistochemical studies in sections from invasive breast carcinoma and ductal carcinoma in situ (DCIS) indicated various levels (from 5 to 400 units) of the M6P/IGF2-R protein, which did not correlate with tumor size, histological grade, estrogen and progesterone receptors. Moreover, the M6P/IGF2-R level was increased in DCIS relative to adjacent normal tissue (p < 0.005) and then decreased in invasive carcinoma compared with DCIS (p < 0.02). The hypothesis of tumor suppressor gene is not supported by these studies. However, it is not excluded for a small proportion of the tumors. Its assay might help to complement the cathepsin D assay to predict breast cancer prognosis and physiopathology.

Mannose-6-Phosphate/Insulin-Like Growth Factor 2 Receptor (M6P/IGF2-R) in Growth and Disease: A Review

“…Studies at the protein level in mammary cancer showed that M6P/IGF2-R levels were significantly lower in cancer cells than in normal cells in 50% of tumors in which the peritumoral normal glands could be quantified in parallel, agreeing the hypothesis of a tumor suppressor gene for the M6P/IGF2-R [76]. Most of further studies led on M6P/IGF2-R suggested M6P/IGF2-R as being coded by a tumor suppressor gene [72,77,78] and its role as a putative prognostic marker in breast cancers has been hypothesized [76].…”

Role of Insulin-Like Growth Factor Receptor 2 across Muscle Homeostasis: Implications for Treating Muscular Dystrophy

“…Some studies have speculated that M6P/IGF2-R, although characterized by a single-spanning structure, might initiate signaling cascades through G-proteins in a direct or indirect manner. It is well known that the pertussis toxin exerts its activity by binding and blocking the activation of the α subunit of the Gq/11-protein [39]. El-Shewy et al showed that the use of this toxin is able to inhibit the function of M6P/IGF2-R, therefore suggesting the involvement of G-proteins in the downstream pathway of M6P/IGF2-R. Pre-treatment of Human embryonic kidney 293 cells (HEK-293) cells with the pertussis toxin can significantly reduce the level of extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation resulting from the interaction of IGFs with their receptors.…”

Introductory Chapter: Genes Expression in the Control of Cell Cycle and Their Potential Value in Cancer Prognosis

“…Therefore, the M6P/IGF2-R has been hypothesized as being coded by a breast cancer suppres sor gene [23], and its potential prognostic significance in breast cancer has been suggested [24].…”