Assessment of the Molecular Heterogeneity of E-Cadherin Expression in Invasive Lobular Breast Cancer

Mutations and loss of E-cadherin protein expression define the vast majority of invasive lobular carcinomas. In a subset of these cases, the heterogeneous expression of E-cadherin is observed either as wild-type (strong membranous) expression or aberrant expression (cytoplasmic expression). However, it is unclear as to whether the two components would be driven by distinct genetic or epigenetic alterations. Here, we used whole genome DNA sequencing and methylation array profiling of two separately dissected components of nine invasive lobular carcinomas with heterogeneous E-cadherin expression. E-cadherin negative and aberrant/positive components of E-cadherin heterogeneous tumours showed a similar mutational, copy number and promoter methylation repertoire, suggesting they arise from a common ancestor, as opposed to the collision of two independent tumours. We found that the majority of E-cadherin heterogeneous tumours harboured CDH1 mutations in both the E-cadherin negative and aberrant/positive components together with somatic mutations in additional driver genes known to be enriched in both pure invasive carcinomas of no special type and invasive lobular breast cancers, whereas these were less commonly observed in CDH1 wild-type tumours. CDH1 mutant tumours also exhibited a higher mutation burden as well as increased presence of APOBEC-dependent mutational signatures 2 and 13 compared to CDH1 wild-type tumours. Together, our results suggest that regardless of E-cadherin protein expression, tumours showing heterogeneous expression of E-cadherin should be considered as part of the spectrum of invasive lobular breast cancers.

The role of AKR1 family in tamoxifen resistant invasive lobular breast cancer based on data mining

Background Tamoxifen (TAM) resistance to invasive lobular cell carcinoma is a challenge for breast cancer treatment. This study explored the role of Aldo-keto reductase family 1 (AKR1) family in tamoxifen-resistant aggressive lobular breast cancer based on data mining. Methods TAM-resistant invasive lobular breast cancer gene chip was downloaded from the Gene Expression Omnibus (GEO) database (accession-numbered as GSE96670). The online analytical tool GEO2R was used to screen for differentially expressed genes in TAM-resistant invasive lobular breast cancer cells and TAM-sensitive counterparts. A protein-protein interaction (PPI) networks were constructed using the STRING online platform and the Cytoscape software. GeneMANIA and GSCALite online tools were used to reveal the potential role of these hub genes in breast cancer progression and TAM resistance development. And the used the GSE67916 microarray data set to verify the differentially expression of these hub genes in breast cancer. The protein expression levels of AKR1C1, AKR1C2 and AKR1C3 in TAM-sensitive and resistant breast cancer cells were compared. The TAM sensitivity of breast cancer cells with or without AKR1C1, AKR1C2 or AKR1C3 gene manipulation was evaluated by cell viability assay. Results A total of 184 differentially expressed genes were screened. Compared with TAM sensitive breast cancer cells, 162 were up-regulated and 22 were down-regulated. The study identified several hub genes in the PPI network that may be involved in the development of TAM resistance of breast cancer, including signal transducer and activator of transcription 1 (STAT1), estrogen receptor alpha (ESR1), fibronectin1 (FN1), cytochrome P4501B1 (CYP1B1), AKR1C1, AKR1C2, AKR1C3 and uridine diphosphate glucuronosyltransferase (UGT) 1A family genes (UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10). Compared with TAM-sensitive counterparts, the expression levels of AKR1C1, AKR1C2, and AKR1C3 were up-regulated in TAM-resistant breast cancer cells. Conclusions Overexpression of each of these three genes significantly increased the resistance of breast cancer cells to TAM treatment, while their knockdown showed opposite effects, indicating that they are potential therapeutic target for the treatment of TAM-resistant breast cancer.

Lobular Breast Cancer Conspicuity on Digital Breast Tomosynthesis Compared to Synthesized 2D Mammography: A Multireader Study

Objectives: To compare the conspicuity of lobular breast cancers at digital breast tomosynthesis (DBT) versus synthesized 2D mammography (synt2D). Materials and methods: Seventy-six women (mean age 61.2 years, range 50–74 years) submitted to biopsy in our institution, from 2019 to 2021, with proven invasive lobular breast cancer (ILC) were enrolled in this retrospective study. The participants underwent DBT and synt2D. Five breast radiologists, with different years of experience in breast imaging, independently assigned a conspicuity score (ordinal 6-point scale) to DBT and synt2D. Lesion conspicuity was compared, for each reader, between the synt2D overall conspicuity interpretation and DBT overall conspicuity interpretation using a Wilcoxon matched pairs test. Results: A total of 50/78 (64%) cancers were detected on both synt2D and DBT by all the readers, while 28/78 (26%) cancers where not recognized by at least one reader on synt2D. For each reader, in comparison with synt2D, DBT increased significantly the conspicuity of ILC (p < 0.0001). The raw proportion of high versus low conspicuity by modality confirmed that cancers were more likely to have high conspicuity at DBT than synt2D. Conclusions: ILCs were more likely to have high conspicuity at DBT than at synt2D, increasing the chances of the detection of ILC breast cancer.