The Genomic Landscape of Lobular Breast Cancer

Reed, Amy E. McCart; Foong, Samuel; Kutasovic, Jamie R.; Nones, Kátia; Waddell, Nicola; Lakhani, Sunil R.; Simpson, Peter T.

doi:10.3390/cancers13081950

Cited by 19 publications

(14 citation statements)

References 49 publications

(94 reference statements)

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“…Although some studies analyzing ILC have reported a similar frequency of CDH1 mutations in ILC, these studies did not select cases based on E-cadherin loss. 18 Our results suggested that mechanisms other than CDH1 mutations are frequently implicated in E-cadherin loss in IDLC.…”

Section: Discussionmentioning

confidence: 53%

The Clonal Relationship Between the Ductal and Lobular Components of Mixed Ductal-Lobular Carcinomas Suggested a Ductal Origin in Most Tumors

Pérez-Míes

Caniego-Casas

Carretero‐Barrio

et al. 2022

American Journal of Surgical Pathology

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The relationship between the ductal and lobular components of invasive ductolobular carcinomas (IDLC) has not been fully elucidated. In this study, the molecular alterations of both components were analyzed in a series of 20 IDLC that were selected, not only by morphologic criteria, but also by the loss of E-cadherin expression in the lobular component. We found that 80% of tumors shared alterations of driver genes in both components, being PIK3CA the most common alteration. In addition, 45% of IDLC carried CDH1 mutations in their lobular component that were absent in the ductal component. Fluorescent in situ hybridization analysis of the CDH1 gene excluded homozygous CDH1 loss as a frequent cause of E-cadherin loss in tumors without CDH1 mutations. In addition, no pathogenic mutations of catenin genes were detected in this series of tumors. In 25% of tumors, actionable mutations in PIK3CA, AKT1, and ERBB2 were found in only 1 component. Altogether, our results confirm that most IDLC derive from invasive carcinoma of no special type, in which a population of cells lose E-cadherin and acquire a lobular phenotype. The frequency of CDH1 mutations in IDLC appears to be lower than in conventional invasive lobular carcinomas, suggesting the implication of alternative mechanisms of E-cadherin loss. Moreover, molecular heterogeneity between ductal and lobular areas suggests the need for molecular characterization of both components to guide targeted therapies.

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Section: Discussionmentioning

confidence: 53%

The Clonal Relationship Between the Ductal and Lobular Components of Mixed Ductal-Lobular Carcinomas Suggested a Ductal Origin in Most Tumors

Pérez-Míes

Caniego-Casas

Carretero‐Barrio

et al. 2022

American Journal of Surgical Pathology

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“…Next, we tested the effect of dasatinib on mammary and gastric organoids lacking both Cdh1 and T p53 expression. These organoids were generated in order to more closely reflect the genetic complexity of advanced DGC and LBC which have Tp53 mutation frequencies of ~33% and ~7–18%, respectively [ 56 , 57 , 58 ]. The difference in the response of Tp53 −/− Cdh1 −/− gastric and mammary organoids to dasatinib was similar to that of Cdh1 −/− organoids ( Figure 4 E,F).…”

Section: Resultsmentioning

confidence: 99%

E-Cadherin-Deficient Cells Are Sensitive to the Multikinase Inhibitor Dasatinib

Bougen-Zhukov

Decourtye-Espiard

Mitchell

et al. 2022

Cancers

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The CDH1 gene, encoding the cell adhesion protein E-cadherin, is one of the most frequently mutated genes in gastric cancer and inactivating germline CDH1 mutations are responsible for the cancer syndrome hereditary diffuse gastric cancer (HDGC). CDH1-deficient gastric cancers exhibit high AKT serine/threonine kinase 3 (AKT3) expression, but specific drugs against this AKT isoform are not available. We therefore used two publicly available datasets to identify AKT3-associated genes which could be used to indirectly target AKT3. Reactome analysis identified an enrichment of extracellular matrix remodelling genes in AKT3-high gastric cancers. Of the 51 genes that were significantly correlated with AKT3 (but not AKT1), discoidin domain receptor tyrosine kinase 2 (DDR2) showed the strongest positive association. Treatment of isogenic human cells and mouse gastric and mammary organoids with dasatinib, a small molecule inhibitor of multiple kinases including SRC, BCR-ABL and DDR2, preferentially slowed the growth and induced apoptosis of E-cadherin-deficient cells. Dasatinib treatment also preferentially slowed the growth of gastric and mammary organoids harbouring both Cdh1 and Tp53 mutations. In organoid models, dasatinib treatment was associated with decreased phosphorylation of total AKT, with a stronger effect seen in Cdh1-deficient organoids. Treatment with combinations of dasatinib and an inhibitor of AKT, MK2206, enhanced the effect of dasatinib in breast MCF10A cells. In conclusion, targeting the DDR2-SRC-AKT3 axis with dasatinib represents a promising approach for the chemoprevention and chemotherapy of gastric and breast cancers lacking E-cadherin.

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“…This has been explained by epigenetic silencing and/or transcriptional repression, but the relevance of these proposed alternative mechanisms has remained controversial [42,87,88]. Lack of a detectable CDH1 mutation may also be related to insufficient sequencing depth or low tumor cellularity [40,89]. In some instances, CDH1 missense mutations, in-frame deletions, and even truncating mutations can be associated with preserved E-cadherin expression [43,90].…”

Section: Ilc As a Morpho-molecular Entitymentioning

confidence: 99%

“…Histological grade G1 is associated with comparatively good short-term outcome, but the prognosis G2-and G3-differentiated cases is difficult to predict [61]. High grade ILC appears to be associated with worse outcome [61,73,89].…”

Section: Classic Ilcmentioning

confidence: 99%

Lobular Breast Cancer: Histomorphology and Different Concepts of a Special Spectrum of Tumors

Christgen

Floris

Marchiò

et al. 2021

Cancers

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Invasive lobular breast cancer (ILC) is the most common special histological type of breast cancer (BC). This review recapitulates developments in the histomorphologic assessment of ILC from its beginnings with the seminal work of Foote and Stewart, which was published in 1941, until today. We discuss different concepts of ILC and their implications. These concepts include (i) BC arising from mammary lobules, (ii) BC growing in dissociated cells and single files, and (iii) BC defined as a morpho-molecular spectrum of tumors with distinct histological and molecular characteristics related to impaired cell adhesion. This review also provides a comprehensive overview of ILC variants, their histomorphology, and differential diagnosis. Furthermore, this review highlights recent advances which have contributed to a better understanding of the histomorphology of ILC, such as the role of the basal lamina component laminin, the molecular specificities of triple-negative ILC, and E-cadherin to P-cadherin expression switching as the molecular determinant of tubular elements in CDH1-deficient ILC. Last but not least, we provide a detailed account of the tumor microenvironment in ILC, including tumor infiltrating lymphocyte (TIL) levels, which are comparatively low in ILC compared to other BCs, but correlate with clinical outcome. The distinct histomorphology of ILC clearly reflects a special tumor biology. In the clinic, special treatment strategies have been established for triple-negative, HER2-positive, and ER-positive BC. Treatment specialization for patients diagnosed with ILC is just in its beginnings. Accordingly, ILC deserves greater attention as a special tumor entity in BC diagnostics, patient care, and cancer research.

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The Genomic Landscape of Lobular Breast Cancer

Cited by 19 publications

References 49 publications

The Clonal Relationship Between the Ductal and Lobular Components of Mixed Ductal-Lobular Carcinomas Suggested a Ductal Origin in Most Tumors

The Clonal Relationship Between the Ductal and Lobular Components of Mixed Ductal-Lobular Carcinomas Suggested a Ductal Origin in Most Tumors

E-Cadherin-Deficient Cells Are Sensitive to the Multikinase Inhibitor Dasatinib

Lobular Breast Cancer: Histomorphology and Different Concepts of a Special Spectrum of Tumors

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