Lobular Breast Cancer: Pathology, Biology, and Options for Clinical Intervention

Vlug, Eva J.; Ercan, Cigdem; Wall, Elsken van der; Diest, Paul J. van; Derksen, Patrick W.B.

doi:10.1007/s00005-013-0251-0

Cited by 18 publications

(16 citation statements)

References 169 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition to the high expression of ERβ in early lobular cancer, another marked difference between lobular and ductal cancer was the lack of proliferating cells in lobular cancer: Ki67-positive cells were very abundant in ductal cancer but very rare in lobular cancer. Thus, our data support the previous conclusion (47,48) that lobular cancer is a disease resulting from resistance to anoikis and not one of proliferation. What was surprising in the present study is the finding that high-grade lobular cancer is characterized by loss of ERβ expression, high ERα level, and high proliferation.…”

Section: Discussionsupporting

confidence: 92%

Differential expression of estrogen receptor α, β1, and β2 in lobular and ductal breast cancer

Huang

Omoto

Iwase

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

150

120

View full text Add to dashboard Cite

The role of estrogen receptor (ER) α as a target in treatment of breast cancer is clear, but those of ERβ1 and ERβ2 in the breast remain unclear. We have examined expression of all three receptors in surgically excised breast samples from two archives: (i): 187 invasive ductal breast cancer from a Japanese study; and (ii) 20 lobular and 24 ductal cancers from the Imperial College. Samples contained normal areas, areas of hyperplasia, and in situ and invasive cancer. In the normal areas, ERα was expressed in not more than 10% of epithelium, whereas approximately 80% of epithelial cells expressed ERβ. We found that whereas ductal cancer is a highly proliferative, ERα-positive, ERβ-negative disease, lobular cancer expresses both ERα and ERβ but with very few Ki67-positive cells. ERβ2 was expressed in 32% of the ductal cancers, of which 83% were postmenopausal. In all ERβ2-positive cancers the interductal space was filled with dense collagen, and cell nuclei expressed hypoxia-inducible factor 1α. ERβ2 expression was not confined to malignant cells but was strong in stromal, immune, and endothelial cells. In most of the high-grade invasive ductal cancers neither ERα nor ERβ was expressed, but in the high-grade lobular cancer ERβ was lost and ERα and Ki67 expression were abundant. The data show a clear difference in ER expression between lobular and ductal breast cancer and suggest (i) that tamoxifen may be more effective in late than in early lobular cancer and (ii) a potential role for ERβ agonists in preventing in situ ductal cancers from becoming invasive.ductal carcinoma in situ | invasive ductal carcinoma | invasive lobular carcinoma

show abstract

Section: Discussionsupporting

confidence: 92%

Differential expression of estrogen receptor α, β1, and β2 in lobular and ductal breast cancer

Huang

Omoto

Iwase

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

150

120

View full text Add to dashboard Cite

show abstract

“…Apart from the obvious EMT hallmark (E-cadherin loss), metastatic cells in these models retained their epithelial characteristics based on luminal cytokeratin expression patterns, and lacked expression of the mesenchymal EMT markers. These findings conform to clinicopathological findings in DGC and ILC, where invading cells and their metastases are luminal epithelial-type cancer cells (Vlug et al 2013a;Mahmud et al 2015;van der Post et al 2015). In sum, these data demonstrate that early mutational loss of E-cadherin does not lead to a classical EMT.…”

Section: E-cadherin Loss and The Epithelial To Mesenchymal Transitionsupporting

confidence: 86%

Loss of E-Cadherin-Dependent Cell–Cell Adhesion and the Development and Progression of Cancer

Bruner

Derksen

2017

Cold Spring Harb Perspect Biol

166

117

View full text Add to dashboard Cite

Classical cadherins are the key molecules that control cell-cell adhesion. Notwithstanding this function, it is also clear that classical cadherins are more than just the "glue" that keeps the cells together. Cadherins are essential regulators of tissue homeostasis that govern multiple facets of cellular function and development, by transducing adhesive signals to a complex network of signaling effectors and transcriptional programs. In cancer, cadherins are often inactivated or functionally inhibited, resulting in disease development and/or progression. This review focuses on E-cadherin and its causal role in the development and progression of breast and gastric cancer. We provide a summary of the biochemical consequences and consider the conceptual impact of early (mutational) E-cadherin loss in cancer. We advocate that carcinomas driven by E-cadherin loss should be considered "actin-diseases," caused by the specific disruption of the E-cadherin-actin connection and a subsequent dependence on sustained actomyosin contraction for tumor progression. Based on the available data from mouse and human studies we discuss opportunities for targeted clinical intervention.

show abstract

“…Anchorage-dependent cell growth was assessed as previously described 5 . In short, cells were grown on 12-well plates incubated with the indicated inhibitors.…”

Section: Methodsmentioning

confidence: 99%

“…Subsequent studies using mouse and human ILC models have shown that tumour progression is in part due to anchorage independence triggered by p120-catenin-dependent activation of RhoA and Rock1 3 , 4 . Loss of E-cadherin expression is observed in the vast majority of lobular breast cancers, mostly due to inactivating CDH1 mutations and subsequent loss of heterozygosity, or epigenetic silencing of the E-cadherin promoter 5 . As a result of E-cadherin inactivation, the adherens junction (AJ) is no longer functional, leading to disruption of epithelial integrity and acquisition of tumour-promoting events such as anchorage independence, angiogenesis and tumour cell invasion 6 .…”

Section: Introductionmentioning

confidence: 99%

E-cadherin loss induces targetable autocrine activation of growth factor signalling in lobular breast cancer

Teo

Gómez-Cuadrado

Tenhagen

et al. 2018

Sci Rep

Self Cite

View full text Add to dashboard Cite

Despite the fact that loss of E-cadherin is causal to the development and progression of invasive lobular carcinoma (ILC), options to treat this major breast cancer subtype are limited if tumours develop resistance to anti-oestrogen treatment regimens. This study aimed to identify clinically targetable pathways that are aberrantly active downstream of E-cadherin loss in ILC. Using a combination of reverse-phase protein array (RPPA) analyses, mRNA sequencing, conditioned medium growth assays and CRISPR/Cas9-based knock-out experiments, we demonstrate that E-cadherin loss causes increased responsiveness to autocrine growth factor receptor (GFR)-dependent activation of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Akt signalling. Autocrine activation of GFR signalling and its downstream PI3K/Akt hub was independent of oncogenic mutations in PIK3CA, AKT1 or PTEN. Analyses of human ILC samples confirmed growth factor production and pathway activity. Pharmacological inhibition of Akt using AZD5363 or MK2206 resulted in robust inhibition of cell growth and survival of ILC cells, and impeded tumour growth in a mouse ILC model. Because E-cadherin loss evokes hypersensitisation of PI3K/Akt activation independent of oncogenic mutations in this pathway, we propose clinical intervention of PI3K/Akt in ILC based on functional E-cadherin inactivation, irrespective of activating pathway mutations.

show abstract

Lobular Breast Cancer: Pathology, Biology, and Options for Clinical Intervention

Cited by 18 publications

References 169 publications

Differential expression of estrogen receptor α, β1, and β2 in lobular and ductal breast cancer

Differential expression of estrogen receptor α, β1, and β2 in lobular and ductal breast cancer

Loss of E-Cadherin-Dependent Cell–Cell Adhesion and the Development and Progression of Cancer

E-cadherin loss induces targetable autocrine activation of growth factor signalling in lobular breast cancer

Contact Info

Product

Resources

About