Immunoexpression of claudins 4 and 7 among invasive breast carcinoma subtypes: A large diagnostic study using tissue microarray

Abstract

Molecular phenotyping and tissue microarray (TMA) studies have identified distinct invasive breast carcinoma subtypes: Luminal A, luminal B, enriched with overexpressed human epidermal growth factor receptor 2 (HER-2) and triple-negative, i.e., negative for HER-2, as well as for estrogen and progesterone receptor (ER and PR, respectively) expression. These subtypes are useful in clinical management, since they bear distinct prognoses and predictive responses to targeted therapy. However, although molecular profiling provides important prognostic indicators, breast cancer risk stratification remains a challenge in triple-negative cases. What is referred to as claudin-low subtype was identified as a triple-negative subset that is associated with more aggressive tumor behavior and worse prognosis. However, the immunohistochemical expression of claudins has not yet been standardized. Our objective was to verify whether the immunoexpression of claudins 4 and 7 (the main claudins specifically expressed in human breast tissue) in TMA is associated with survival and prognosis in luminal A, HER-2 and triple-negative molecular subtypes. In this diagnostic study, we investigated ER/PR receptor status, HER-2, claudin 4 and 7 expression and stem cell CD44/24 profiles, and verified the association with prognosis and survival outcomes in 803 invasive breast carcinoma cases arranged in four TMAs. Among these, 503 (62.6%) were positive for claudin 4 and 369 (46.0%) for claudin 7. Claudin 4 exhibited the lowest expression in luminal A and triple-negative subtypes, and the highest frequency of expression in HER-2-enriched subtypes, whereas claudin 7 staining was not associated with any subtype. The stem cell phenotype was not associated with subgroups or claudins 4 and 7. Claudin immunoexpression profile was not able to distinguish between patients with better or worse prognosis, and it was not correlated to triple-negative cases. Therefore, it may be concluded that the immunoexpression of claudins 4 and 7, individually or within the usual immunohistochemical context (ER, PR and HER-2), does not provide additional prognostic information on breast cancer subtypes.

Profiling the expression of pro-metastatic genes in association with the clinicopathological features of primary breast cancer

“…The overexpression of CLDN-4 was observed in patients with lymphatic metastasis subgroup which is in agreement with previous reports of BrCa patients [ 19 , 41 ]. The CLDN - 4 -dependent up-regulation of matrix metalloproteinase (MMP)-2 and MMP-9 and increased invasiveness might be another clue responsible for lymphatic metastasis [ 61 ].…”

“…Akimoto et al [ 90 ] represented a positive correlation between the activity of estrogen-dependent G protein-coupled receptor 30/Akt-related pathway and CLDN - 1 expression in cervical adenocarcinoma cells [ 90 ]. The contradictory results from studies which addressed CLDNs expression concerning molecular subtypes [ 35 – 38 , 40 , 41 , 43 , 44 ], present findings could add an insight focusing on the association of CLDN - 1 - CLDN - 4 and ROCK - CLDN - 2 connected to breast tumors characterized by hormone receptor-positive.…”

“…No study reported a significant correlation between CLDN-2 expression and histologic grade and tumor size of BrCa patients. Several reports indicated a positive protein expression of CLDN-4 connected to poor prognosis [ 37 , 40 ], advanced grade [ 37 , 40 – 43 ], and lymphatic metastasis [ 19 , 41 ] of BrCa. However, positive or negative protein expression of CLDN-4 was reported to be correlated to a larger tumor size of BrCa [ 37 , 43 ].…”

“…However, positive or negative protein expression of CLDN-4 was reported to be correlated to a larger tumor size of BrCa [ 37 , 43 ]. CLDNs expression was dependent on the molecular subtypes of breast tumors [ 35 – 38 , 40 , 41 , 43 , 44 ]. The data on the association of CLDNs expression and clinicopathological parameters remains inconclusive.…”

Inhibition of interferon-signalling halts cancer-associated fibroblast-dependent protection of breast cancer cells from chemotherapy

“…The claudin-low breast cancer subtype was identified more than a decade ago 40 , however claudin expression levels are not assessed in routine breast cancer management since they have not been found to be useful in directing treatment choices to improve outcomes 41 .…”