Previously, we showed that pure ductal carcinoma in situ (DCIS) of the breast can be divided into 3 subtypes (luminal, basal/stem, and null) based on the expression of 5 cytokeratin (CK) markers: CK5/6, CK14, CK17 (stem/basal), and CK8, CK18 (luminal). The distributions of CK subtypes were associated with nuclear grade and differential expression of estrogen receptor-alpha (ER-alpha), progesterone receptor (PR), HER-2/neu, and epidermal growth factor receptor (EGFR). In this study, we further explore the expression patterns of CK markers, ER-alpha, PR, HER-2/neu, and EGFR by immunohistochemical (IHC) analysis of 99 cases of pure DCIS and 96 cases of DCIS with co-existing invasive ductal carcinoma (DCIS/IDC). We show that between high-grade DCIS and DCIS/IDC, there are differential expression patterns for ER-alpha, PR, and EGFR in corresponding CK subtypes, suggesting that at least some pure DCIS is molecularly distinct from DCIS/IDC. In most cases there is a high degree of co-expression of these markers between DCIS and the co-existing IDC, suggesting that DCIS is frequently a precursor lesion for co-existing IDC. The rate of discordant expression of these markers is low and is more frequently associated with high-grade carcinoma, suggesting that other molecular pathways also may also be present. There are significant differences in the expression of these molecular markers between high-grade and non-high-grade carcinomas, supporting the view that high-grade and non-high-grade carcinomas of the breast are molecularly distinct entities.
"DCIS is found adjacent to invasive disease in the vast majority of IBCs at the time of diagnosis (Evans et al., 1997; Fisher et al., 1975), where it was thought to be the precursor lesion, however the coexistence of DCIS with IBC varies according to the subtype of breast cancer (Abdel-Fatah et al., 2007). DCIS can be classified into similar molecular subtypes as IBC based primarily on the expression patterns of ER, PR, HER2, EGFR and cytokeratin 5/6 (Bryan et al., 2006; Clark et al., 2011; Livasy et al., 2007; Muggerud et al., 2010), and associated in situ and invasive components often, but not always (see below), exhibit a similar immunophenotype (Steinman et al., 2007; Tamimi et al., 2008). Also, nuclear grade is generally concordant between in situ and invasive components of invasive carcinomas, which have comparable nuclear morphology (Giardina et al., 2003) and DNA ploidy (Ottesen, 2003). "
[Show abstract][Hide abstract] ABSTRACT: Ductal carcinoma in situ (DCIS) is an intraductal neoplastic proliferation of epithelial cells that is separated from the breast stroma by an intact layer of basement membrane and myoepithelial cells. DCIS is a non-obligate precursor of invasive breast cancer, and up to 40% of these lesions progress to invasive disease if untreated. Currently, it is not possible to predict accurately which DCIS would be more likely to progress to invasive breast cancer as neither the significant drivers of the invasive transition have been identified, nor has the clinical utility of tests predicting the likelihood of progression been demonstrated. Although molecular studies have shown that qualitatively, synchronous DCIS and invasive breast cancers are remarkably similar, there is burgeoning evidence to demonstrate that intra-tumor genetic heterogeneity is observed in a subset of DCIS, and that the process of progression to invasive disease may constitute an 'evolutionary bottleneck', resulting in the selection of subsets of tumor cells with specific genetic and/or epigenetic aberrations. Here we review the clinical challenge posed by DCIS, the contribution of the microenvironment and genetic aberrations to the progression from in situ to invasive breast cancer, the emerging evidence of the impact of intra-tumor genetic heterogeneity on this process, and strategies to combat this heterogeneity.
[Show abstract][Hide abstract] ABSTRACT: Background
This study aimed to evaluate the relationship between the molecular phenotype of the primary mammary tumor and its related lymph node metastasis in the dog to develop prognostic-predictive models and targeted therapeutic options.
Twenty mammary tumor samples and their lymph node metastases were selected and stained by immunohistochemistry with anti-estrogen receptor (ER), -progesterone receptor (PR), -human epidermal growth factor receptor 2 (c-erbB-2), -cytokeratin 5/6 (CK 5/6), -cytokeratin 14 (CK14), -cytokeratin 19 (CK 19) and -protein 63 (p63) antibodies. Four phenotypes (luminal A, luminal B, c-erbB2 overexpressing and basal-like) were diagnosed in primary tumors and five (luminal A, luminal B, c-erbB-2 overexpressing, basal-like and normal-like) in the lymph node metastases. Phenotypic concordance was found in 13 of the 20 cases (65%), and seven cases (35%) showed discordance with different lymph node phenotypic profile from the primary tumor.
The phenotype of the primary tumor assumes a predictive-therapeutic role only in concordant cases, meaning that both the primary tumor and its lymph node metastasis should be evaluated at the same time. A treatment plan based only on the primary tumor phenotype could lead to therapeutic failures if the phenotype of the lymph node metastasis differs from that of the primary tumor.
BMC Veterinary Research 11/2012; 8(1):219. DOI:10.1186/1746-6148-8-219 · 1.78 Impact Factor
"In an effort to develop a similar classification that is clinically significant, technically simple, reproducible and readily available, several IHC-based molecular classifications for breast cancer have been investigated extensively. These include: 1) Cytokeratin-based classification divides breast carcinomas into basal subtype (CK5/6, CK14, CK17 positive), and luminal subtype (CK8, CK18 positive and basal negative);29–33 2) ER, PR and HER2-based classification defines the basal subtype as an absence of expression of ER, PR and HER2;34–38 3) ER, HER2, EGFR and CK5/6-based classification22,39 defines the basal subtype as ER and HER2 negative, and CK5/6 and/or EGFR positive, with 76% sensitivity and 100% specificity, respectively, compared to basal subtype defined by gene expression profiling. Although these IHC-based molecular classifications all show basal subtype has the worse prognosis, they are not interchangeable.40 "
[Show abstract][Hide abstract] ABSTRACT: The expression of basal cytokeratin markers CK5/6 in breast carcinomas has been associated with high histological grade and poor clinical outcome. A previous study has shown that CK5/6 can be detected in up to 17% of invasive lobular carcinomas (ILC). Here we study the expression of three basal cytokeratin markers (CK5/6, CK14, and CK17) in 53 ILC cases diagnosed by histology and lack of E-cadherin expression. Among them, 42 were classic lobular carcinomas, 6 were tubular-lobular carcinoma, and 5 were pleomorphic lobular carcinomas. There was no significant difference among these three groups in patients' age, tumor size, uni- and multi-focality, expression of ER and PR, lymphovascular invasion, perineural invasion and lymph node metastasis. The only statistically different factor was HER2 over-expression, which was observed only in pleomorphic ILC (P = 0.0073). None of the 53 cases expressed CK5/6, CK14 or CK17; and 51/53 cases expressed luminal markers CK8 and CK18, and the two negative cases were both classic lobular carcinoma, with positivity for ER and PR. In conclusion, all 53 cases of ILC failed to show expression by any of the three basal CK markers, suggesting that very few ILC will demonstrate a basal phenotype when assessed by immunohistochemistry (IHC). More studies are needed to investigate molecular classification in lobular carcinoma of the breast.
Breast cancer 10/2010; 4(1):49-55. DOI:10.4137/BCBCR.S5037
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