An epithelial to mesenchymal transition programme does not usually drive the phenotype of invasive lobular carcinomas

Reed, Amy E. McCart; Kutasovic, Jamie R.; Vargas, Ana Cristina; Jayanthan, Janani; Al‐Murrani, Amel; Reid, Lynne; Chambers, Rachael; Silva, Leonard Da; Melville, Lewis; Evans, Elizabeth; Porter, Alan; Papadimos, David; Thompson, Erik W.; Lakhani, Sunil R.; Simpson, Peter T.

doi:10.1002/path.4668

Cited by 37 publications

(26 citation statements)

References 23 publications

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“…We compared patterns of E‐cadherin complex expression between lobular components of the MDLs with a cohort of 148 pure ILCs and associated LCISs . Both in situ and invasive components of pure ILCs showed loss of E‐cadherin and β‐catenin significantly more frequently than the lobular components of MDLs; conversely, the lobular components of MDLs showed aberrant expression of the complex significantly more frequently than pure ILCs (Figure B; p < 0.0001).…”

Section: Resultsmentioning

confidence: 99%

Mixed ductal‐lobular carcinomas: evidence for progression from ductal to lobular morphology

Reed

Kutasovic

Nones

et al. 2018

The Journal of Pathology

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Mixed ductal–lobular carcinomas (MDLs) show both ductal and lobular morphology, and constitute an archetypal example of intratumoural morphological heterogeneity. The mechanisms underlying the coexistence of these different morphological entities are poorly understood, although theories include that these components either represent ‘collision’ of independent tumours or evolve from a common ancestor. We performed comprehensive clinicopathological analysis of a cohort of 82 MDLs, and found that: (1) MDLs more frequently coexist with ductal carcinoma in situ (DCIS) than with lobular carcinoma in situ (LCIS); (2) the E‐cadherin–catenin complex was normal in the ductal component in 77.6% of tumours; and (3) in the lobular component, E‐cadherin was almost always aberrantly located in the cytoplasm, in contrast to invasive lobular carcinoma (ILC), where E‐cadherin is typically absent. Comparative genomic hybridization and multiregion whole exome sequencing of four representative cases revealed that all morphologically distinct components within an individual case were clonally related. The mutations identified varied between cases; those associated with a common clonal ancestry included BRCA2, TBX3, and TP53, whereas those associated with clonal divergence included CDH1 and ESR1. Together, these data support a model in which separate morphological components of MDLs arise from a common ancestor, and lobular morphology can arise via a ductal pathway of tumour progression. In MDLs that present with LCIS and DCIS, the clonal divergence probably occurs early, and is frequently associated with complete loss of E‐cadherin expression, as in ILC, whereas, in the majority of MDLs, which present with DCIS but not LCIS, direct clonal divergence from the ductal to the lobular phenotype occurs late in tumour evolution, and is associated with aberrant expression of E‐cadherin. The mechanisms driving the phenotypic change may involve E‐cadherin–catenin complex deregulation, but are yet to be fully elucidated, as there is significant intertumoural heterogeneity, and each case may have a unique molecular mechanism. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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Section: Resultsmentioning

confidence: 99%

Mixed ductal‐lobular carcinomas: evidence for progression from ductal to lobular morphology

Reed

Kutasovic

Nones

et al. 2018

The Journal of Pathology

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“…We also cannot exclude the contributions of other mechanisms of metastasis driving this pattern of dissemination, such as tumour dormancy , or microenvironmental cues from the bone marrow or ‘pre‐metastatic niche’ ; it is unlikely that the mechanisms are mutually exclusive. Epithelial to mesenchymal transition is not a defining feature of ILC and may play a less overt role in this context.…”

Section: Discussionmentioning

confidence: 99%

Breast cancer metastasis to gynaecological organs: a clinico‐pathological and molecular profiling study

Kutasovic

Reed

Males

et al. 2018

The Journal of Pathology CR

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Breast cancer metastasis to gynaecological organs is an understudied pattern of tumour spread. We explored clinico‐pathological and molecular features of these metastases to better understand whether this pattern of dissemination is organotropic or a consequence of wider metastatic dissemination. Primary and metastatic tumours from 54 breast cancer patients with gynaecological metastases were analysed using immunohistochemistry, DNA copy‐number profiling, and targeted sequencing of 386 cancer‐related genes. The median age of primary tumour diagnosis amongst patients with gynaecological metastases was significantly younger compared to a general breast cancer population (46.5 versus 60 years; p < 0.0001). Median age at metastatic diagnosis was 54.4, time to progression was 4.8 years (range 0–20 years), and survival following a diagnosis of metastasis was 1.95 years (range 0–18 years). Patients had an average of five involved sites (most frequently ovary, fallopian tube, omentum/peritoneum), with fewer instances of spread to the lungs, liver, or brain. Invasive lobular histology and luminal A‐like phenotype were over‐represented in this group (42.8 and 87.5%, respectively) and most patients had involved axillary lymph nodes (p < 0.001). Primary tumours frequently co‐expressed oestrogen receptor cofactors (GATA3, FOXA1) and harboured amplifications at 8p12, 8q24, and 11q13. In terms of phenotype conversion, oestrogen receptor status was generally maintained in metastases, FOXA1 increased, and expression of progesterone receptor, androgen receptor, and GATA3 decreased. ESR1 and novel AR mutations were identified. Metastasis to gynaecological organs is a complication frequently affecting young women with invasive lobular carcinoma and luminal A‐like breast cancer, and hence may be driven by sustained hormonal signalling. Molecular analyses reveal a spectrum of factors that could contribute to de novo or acquired resistance to therapy and disease progression.

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“…Lobular breast carcinoma is marked by mutations or loss of E‐cadherin, a critical epithelial protein. Yet, tumor cells within the primary tumor or metastatic lesion do not exhibit complete conversion to a mesenchymal state although these tumors are marked by an invasive growth pattern (McCart Reed et al ., ). Analysis of tumor cells invading through the blood is consistent with these findings.…”

Section: Functional Characteristics Of Epithelial and Mesenchymal Ctcmentioning

confidence: 97%

Cancer metastasis through the prism of epithelial‐to‐mesenchymal transition in circulating tumor cells

2017

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Metastasis of epithelial cancer cells to distant sites is a particularly critical stage of cancer progression that typically marks the incurability of the disease. It is governed by a complex series of events including invasion and intravasation of tumor cells into the stroma and blood, respectively. Epithelial‐to‐mesenchymal transition (EMT), a phenotypic change marked by the loss of epithelial characteristics and the acquisition of invasive mesenchymal properties, is implicated in the dissemination of tumor cells. Circulating tumor cells (CTCs), the precursors of metastasis, can be used to interrogate the contribution of EMT in metastasis and therapeutic responses. The analysis of these CTCs and in particular the presence of inter‐ and intrapatient heterogeneity for markers of EMT has provided new insights into the metastatic process. This review will focus on epithelial–mesenchymal plasticity in CTCs and its potential clinical implications.

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An epithelial to mesenchymal transition programme does not usually drive the phenotype of invasive lobular carcinomas

Cited by 37 publications

References 23 publications

Mixed ductal‐lobular carcinomas: evidence for progression from ductal to lobular morphology

Mixed ductal‐lobular carcinomas: evidence for progression from ductal to lobular morphology

Breast cancer metastasis to gynaecological organs: a clinico‐pathological and molecular profiling study

Cancer metastasis through the prism of epithelial‐to‐mesenchymal transition in circulating tumor cells

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