Cell polarity and cell adhesion associated gene expression differences between invasive micropapillary and no special type breast carcinomas and their prognostic significance

Abstract

Invasive micropapillary carcinoma of the breast (IMPC) has been in the focus of several studies given its specific histology and clinicopathological course. We analysed mRNA expression profiles and the prognostic value of 43 genes involved in cell polarity, cell-adhesion and epithelial–mesenchymal transition (EMT) in IMPC tumors and compared them to invasive breast carcinomas of no special type (IBC-NST). IMPCs (36 cases), IBC-NSTs (36 cases) and mixed IMPC-IBC NSTs (8 cases) were investigated. mRNA expression level of selected genes were analysed using the NanoString nCounter Analysis System. Distant metastases free survival (DMFS) intervals were determined. Statistical analysis was performed using Statistica 13.5 software. Twelve genes showed significantly different expression in the IMPC group. There was no difference in DMFS according to histological type (IBC-NST vs. IMPC). High CLDN3, PALS1 and low PAR6 expression levels in the entire cohort were associated with shorter DMFS, and PALS1 was proven to be grade independent prognostic factor. Positive lymph node status was associated with higher levels of AKT1 expression. Differences in gene expression in IMPC versus IBC-NST may contribute to the unique histological appearance of IMPCs. No marked differences were observed in DMFS of the two groups. Altered gene expression in the mTOR signaling pathway in both tumor subtypes highlights the potential benefit from AKT/mTOR inhibitors in IMPCs similarly to IBC-NSTs.

Molecular Pathology of Micropapillary Carcinomas: Is Characteristic Morphology Related to Molecular Mechanisms?

“…Significant differences have been identified in mRNA expressions of integrin-β1 (ITGB1), integrin-α1 (ITGA1), RAC1, CLDN1, SLUG/SNAI2, ZEB1, DLG1, CLDN4, CDH1 (E-cadherin), OCLN, CLDN7, AFDN/ AF6, CLDN3, LIN7A which are effective in cell polarity in MPCs (Table 3). 59,60 Integrin is a protein that forms the glandular lumen and maintains polarity in epithelial cells. Its aberrant expression is associated with adhesion, angiogenesis, tumor progression, and metastasis.…”

“…Claudins are integral membrane proteins, and CLDN1, CLDN3, CLDN4, and CLDN7 significantly lower expression levels are shown in IMPC cases. 59 The Crumbs complex plays an essential role in the apical polarity complex. PALS (proteins associated with LIN7) and PATJ (Pals1-associated tight junction) are the proteins that make up this complex.…”

“…It has been determined that the LIN7A gene is overexpressed in IMPCs, and this expression has a role in the invasion and loss of apicobasal polarity. 59,65 Interestingly, LIN7A is required for human epidermal growth factor receptor 2 (HER2) localization on the basolateral surface of cells. Micropapillary areas may show loss of HER2 expression concerning LIN7A, and a lower HER2 score can be seen immunohistochemically.…”

“…This finding suggests that IMPC tumor cell clusters appear in a highly epithelial state and that these tumor cells form clusters during the stromal invasion and metastasis for- mation rather than using the traditional EMT pathway used by IBC-NSTs. 59 Jagged-1 is the most critical ligand in the Notch signaling pathway and has been associated with poor prognosis and metastasis in breast carcinomas. Jagged-1 regulates EMT by reducing E-cadherin expression.…”

Micropapillary Breast Carcinoma: From Molecular Pathogenesis to Prognosis

“…A recent study by Kramer et al showed that IMPC tumor cells were in a highly epithelial state and did not use the EMT pathway, but rather form cell clusters during invasion and metastasis. 82 …”