https://www.cell.com/cell/pdf/S0092-8674(04)00576-8.pdf

Twist, a Master Regulator of Morphogenesis, Plays an Essential Role in Tumor Metastasis

Tumor metastasis is a multistep process by which tumor cells disseminate from their primary site and form secondary tumors at a distant site. Metastasis occurs through a series of steps: local invasion, intravasation, transport, extravasation, and colonization. A developmental program termed epithelial-mesenchymal transition (EMT) has been shown to play a critical role in promoting metastasis in epithelium-derived carcinoma. Recent experimental and clinical studies have improved our knowledge of this dynamic program and implicated EMT and its reverse program, mesenchymal-epithelial transition (MET), in the metastatic process. Here, we review the functional requirement of EMT and/or MET during the individual steps of tumor metastasis and discuss the potential of targeting this program when treating metastatic diseases.

/pdf/epithelial-mesenchymal-plasticity-in-carcinoma-metastasis-488cf810g8.pdf

Epithelial–mesenchymal plasticity in carcinoma metastasis

We review the role of cadherins and cadherin-related proteins in human cancer. Cellular and animal models for human cancer are also dealt with whenever appropriate. E-cadherin is the prototype of the large cadherin superfamily and is renowned for its potent malignancy suppressing activity. Different mechanisms for inactivating E-cadherin/CDH1 have been identified in human cancers: inherited and somatic mutations, aberrant protein processing, increased promoter methylation, and induction of transcriptional repressors such as Snail and ZEB family members. The latter induce epithelial mesenchymal transition, which is also associated with induction of "mesenchymal" cadherins, a hallmark of tumor progression. VE-cadherin/CDH5 plays a role in tumor-associated angiogenesis. The atypical T-cadherin/CDH13 is often silenced in cancer cells but up-regulated in tumor vasculature. The review also covers the status of protocadherins and several other cadherin-related molecules in human cancer. Perspectives for emerging cadherin-related anticancer therapies are given.

/pdf/involvement-of-members-of-the-cadherin-superfamily-in-cancer-3zuzsjo3pt.pdf

Involvement of Members of the Cadherin Superfamily in Cancer

Snail is a zinc finger transcription factor that triggers the epithelial-mesenchymal transition (EMT) by directly repressing E-cadherin expression. Snail is required for mesoderm and neural crest formation during embryonic development and has recently been implicated in the EMT associated with tumour progression. In a series of human breast carcinomas, we have analysed the expression of Snail and that of molecules of the E-cadherin/catenin complexes. We have also correlated these data with the pathological features of the tumours. We show that Snail expression inversely correlates with the grade of differentiation of the tumours and that it is expressed in all the infiltrating ductal carcinomas (IDC) presenting lymph node metastases that were analysed. In addition, Snail is expressed in some dedifferentiated tumours with a negative nodal status. Considering that Snail is involved in the induction of the invasive and migratory phenotype in epithelial cells, these results indicate that it is also involved in the progression of breast ductal tumours, where it could additionally serve as a marker of the metastatic potential.

Correlation of Snail expression with histological grade and lymph node status in breast carcinomas.

Molecular analysis of invasive breast cancer and its precursors has furthered our understanding of breast cancer progression. In the past few years, new multi-step pathways of breast cancer progression have been delineated through genotypic-phenotypic correlations. Nuclear grade, more than any other pathological feature, is strongly associated with the number and pattern of molecular genetic abnormalities in breast cancer cells. Thus, there are two distinct major pathways to the evolution of low- and high-grade invasive carcinomas: whilst the former consistently show oestrogen receptor (ER) and progesterone receptor (PgR) positivity and 16q loss, the latter are usually ER/PgR-negative and show Her-2 over-expression/amplification and complex karyotypes. The boundaries between the evolutionary pathways of well-differentiated/low-grade ductal and lobular carcinomas have been blurred, with changes in E-cadherin expression being one of the few distinguishing features between the two. In addition, lesions long thought to be precursors of breast carcinomas, such as hyperplasia of usual type, are currently considered mere risk indicators, whilst columnar cell lesions are now implicated as non-obligate precursors of atypical ductal hyperplasia (ADH) and well-differentiated ductal carcinoma in situ (DCIS). However, only through the combination of comprehensive morphological analysis and cutting-edge molecular tools can this knowledge be translated into clinical practice and patient management. Copyright (C) 2005 Pathological Society of Great Britain and Ireland. Published by John Wiley Sons, Ltd.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/path.1691

Molecular evolution of breast cancer

The cell-cell adhesion receptor gene E-cadherin (CDH1) is expressed by epithelial cells, in which it mediates adhesion and morphogenesis. Invasive lobular carcinoma (ILC) characteristically infiltrates diffusely as single cells; by immunohistochemistry, many of these tumours lack E-cadherin expression. In the present study we investigated various ways in which loss of function of the E-cadherin gene could occur in ILCs, namely, promoter methylation, mutation and allelic loss. We analysed 22 ILCs and found 12 (55%) E-cadherin-negative samples by immunohistochemical analysis. Methylation-specific polymerase chain reaction (PCR) showed that 17/22 (77%) of these tumours had methylation of the CDH1 promoter, including 11/12 (91%) of the E-cadherin-negative tumours. All 16 exons of E-cadherin (including intron-exon boundaries) were amplified from chromosomal DNA and screened for mutations by conformation-sensitive gel electrophoresis (CSGE). Bands with altered mobility were analysed by direct sequencing. We identified five frameshift mutations, which resulted in downstream stop codons and one splice site mutation in six different tumours (29%). Loss of heterozygosity (LOH) was assessed using microsatellite markers, and 9/18 (50%) informative tumours showed LOH. We conclude that most ILCs show genetic or epigenetic changes affecting the E-cadherin gene and that many of these tumours lack E-cadherin expression. In all cases in which there was loss of expression, this was consistent with biallelic inactivation of CDH1 by promoter methylation, mutation or allelic loss in any combination.

Multiple ways of silencing E-cadherin gene expression in lobular carcinoma of the breast.


 INTRODUCTION Oncoplastic breast surgery (OPS), has widened the scope of breast conserving surgery (BCS) enabling larger resections with acceptable oncological safety and cosmetic outcomes. It often involves longer incisions and additional contralateral symmetrization procedures on the normal breast. However, patient’s perceptions on outcome may differ from that of the clinician and it is essential to evaluate feedback from patients undergoing OPS to determine the acceptability of these complex procedures in clinical practice. In this regard Health-related quality of life measures (HR-QoL) are an excellent means of evaluating the outcome of medical care. Further, it is well known that socio-cultural differences may reflect on the attitude of patients to treatment outcome and most of the data on OPS and HR-QoL available reflect western thought processes. Based on the feedback of our patients we designed a simple and practical patient-reported outcome measure (PROM) questionnaire reflecting the important issues as voiced by our patients and validated it using the QQ-10, indicating good face validity and acceptability of our questionnaire. We undertook this study to understand the acceptability of OPS level I and II procedures and to determine the satisfaction with the cosmetic outcome as well as the need for contralateral symmetrization procedures in our patients. PATIENTS AND METHODS Based on patient feedback, a questionnaire (Q-IN) was developed and validated by the QQ-10. It includes 9 questions reflecting three domains of general acceptability of the procedure, satisfaction with cosmetic outcome and degree of functional impairment in terms of altered sensation. 126 patients with breast cancer who underwent OPS level I or II without contralateral symmetrization were included in the study. Q-IN was self-administered during routine follow-up, following surgery, between January 2017 and December 2018. It was validated by 31 patients (24.6%)who also answered the QQ-10, a questionnaire designed to assess patients’ views on their experience of using PROM questionnaires during their medical care. The mean value score of the Q-IN as per the QQ-10 was high (84.79%, SD 11.7%) and mean burden score was low (20.96%, SD 24.6%) indicating that it has good face validity and is relevant and acceptable to our patients.RESULTS Mean age of patients was 51 years (21-77 years) and median follow up was 41 months (2- 156 months) following OPS. Majority of patients 124 (98%) were happy about undergoing BCS and had no doubts about the procedure. Most, 115 (91%) were very happy with the cosmetic appearance (shape, size and overall appearance) of the breast after OPS, 10 (8%) were happy and 1 patient (1%) was unhappy. Although most, 103 (81.7%) women, noticed a difference in size the majority 92 (89.3%) felt it was minimal and only 8 (7.8%) found a major difference in size. Of the 78 (61.9%) women that felt a difference in shape, 63 (80.8%) felt it was minimal and 11 (14.1%) reported a major difference. The quality of life of 23 (18.3%) patients was affected by the change in shape and size of the breast. Of these 17(74 %) only thought about the change in appearance, and in 6 (26%) it made a minor difference. Breast sensation was altered in 76 (63.3%) women and that of the nipple-areola complex (NAC) in 77 (58.7%). Of them, 25 (32.9%) reported no sensation in the breast and 30 (40.5%) felt no sensation in the NAC. When asked about a contralateral symmetrization procedure on the normal breast, only 2 (2%) said they would want to undergo symmetrization surgery. CONCLUSIONS Most patients undergoing level I or II oncoplastic breast surgery are happy and satisfied with the overall cosmetic and functional outcome. Only 2% of patients would like to undergo a contralateral symmetrization procedure to match the operated breast.
 Citation Format: Vinay Deshmane, Anuja Raniwala, Clotilda Cardoza. Patient-reported outcome after oncoplastic breast conservation surgery using level I or II techniques without contralateral symmetrization [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-11-35.

Abstract P4-11-35: Patient-reported outcome after oncoplastic breast conservation surgery using level I or II techniques without contralateral symmetrization

Vinay Deshmane

Papers

Multiple ways of silencing E-cadherin gene expression in lobular carcinoma of the breast.

Abstract P4-11-35: Patient-reported outcome after oncoplastic breast conservation surgery using level I or II techniques without contralateral symmetrization