Atypical ductal hyperplasia: update on diagnosis, management, and molecular landscape

Kader, Tanjina; Hill, Prue; Rakha, Emad A.; Gorringe, Kylie L.

doi:10.1186/s13058-018-0967-1

Cited by 52 publications

(33 citation statements)

References 78 publications

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“…3), the study is not able to access the utility of the signature in assigning risk. Larger cohorts of pure AH with follow-up of > 20 years for validation of predictive signatures are needed to identify women with AH who will benefit from interventions and reduce the potential for overtreatment [2].…”

Section: Discussionmentioning

confidence: 99%

“…The 10-year risk of progression to invasive cancer is estimated to be 7% for all AH [1] with a cumulative incidence approaching 35% at 30 years. The overall risk of developing breast cancer is increased by ~ 4-fold among women with atypia and is similar for both ductal and lobular lesions [1, 2]. However, the risk is most prominent among women with higher breast density [3] suggesting that mechanisms underlying breast density affect the progression of premalignant breast lesions.…”

Section: Introductionmentioning

confidence: 99%

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Gene expression signature of atypical breast hyperplasia and regulation by SFRP1

et al. 2019

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Background: Atypical breast hyperplasias (AH) have a 10-year risk of progression to invasive cancer estimated at 4-7%, with the overall risk of developing breast cancer increased by~4-fold. AH lesions are estrogen receptor alpha positive (ERα+) and represent risk indicators and/or precursor lesions to low grade ERα+ tumors. Therefore, molecular profiles of AH lesions offer insights into the earliest changes in the breast epithelium, rendering it susceptible to oncogenic transformation. Methods: In this study, women were selected who were diagnosed with ductal or lobular AH, but no breast cancer prior to or within the 2-year follow-up. Paired AH and histologically normal benign (HNB) tissues from patients were microdissected. RNA was isolated, amplified linearly, labeled, and hybridized to whole transcriptome microarrays to determine gene expression profiles. Genes that were differentially expressed between AH and HNB were identified using a paired analysis. Gene expression signatures distinguishing AH and HNB were defined using AGNES and PAM methods. Regulation of gene networks was investigated using breast epithelial cell lines, explant cultures of normal breast tissue and mouse tissues. Results: A 99-gene signature discriminated the histologically normal and AH tissues in 81% of the cases. Network analysis identified coordinated alterations in signaling through ERα, epidermal growth factor receptors, and androgen receptor which were associated with the development of both lobular and ductal AH. Decreased expression of SFRP1 was also consistently lower in AH. Knockdown of SFRP1 in 76N-Tert cells resulted altered expression of 13 genes similarly to that observed in AH. An SFRP1-regulated network was also observed in tissues from mice lacking Sfrp1. Re-expression of SFRP1 in MCF7 cells provided further support for the SFRP1-regulated network. Treatment of breast explant cultures with rSFRP1 dampened estrogen-induced progesterone receptor levels. Conclusions: The alterations in gene expression were observed in both ductal and lobular AH suggesting shared underlying mechanisms predisposing to AH. Loss of SFRP1 expression is a significant regulator of AH transcriptional profiles driving previously unidentified changes affecting responses to estrogen and possibly other pathways. The gene signature and pathways provide insights into alterations contributing to AH breast lesions.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Gene expression signature of atypical breast hyperplasia and regulation by SFRP1

et al. 2019

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“…The pre-invasive lesions in ductal carcinoma are categorized as either atypical ductal hyperplasia (ADH) or ductal carcinoma in situ (DCIS). It can be difficult to histologically distinguish ADH lesions from that of low-grade DCIS, as the lesions look similar and ADH is mostly identified through failing to meeting the diagnostic criteria for DCIS [3,4]. Ducts exhibiting abnormal proliferation that receive a diagnosis of ADH are partially or completely filled with uniform and polarized cells.…”

Section: Lesions Of the Breastmentioning

confidence: 99%

The Immune Microenvironment of Breast Cancer Progression

Tower

Ruppert

Britt

2019

Cancers

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Inflammation is now recognized as a hallmark of cancer. Genetic changes in the cancer cell are accepted as the match that lights the fire, whilst inflammation is seen as the fuel that feeds the fire. Once inside the tumour, the immune cells secrete cytokines that kick-start angiogenesis to ferry in much-needed oxygen and nutrients that encourage the growth of tumours. There is now irrefutable data demonstrating that the immune contexture of breast tumours can influence growth and metastasis. A higher immune cell count in invasive breast cancer predicts prognosis and response to chemotherapy. We are beginning now to define the specific innate and adaptive immune cells present in breast cancer and their role not just in the progression of invasive disease, but also in the development of pre-invasive lesions and their transition to malignant tumours. This review article focusses on the immune cells present in early stage breast cancer and their relationship with the immunoediting process involved in tumour advancement.

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“…The current model for breast cancer progression proposes independent ‘low grade‐like’ and ‘high grade‐like’ pathways , where low‐grade (LG) and high‐grade (HG) invasive ductal carcinoma (IDC) progress from LG and HG ductal carcinoma in situ (DCIS), respectively . Atypical ductal hyperplasia (ADH) is a common lesion associated with up to a 30% life‐time risk of metachronous breast cancer . ADH occurs within terminal ductal lobular units (TDLUs) and appears as a proliferation of evenly spaced monomorphic epithelial cells that have well‐defined cell borders and generally rounded nuclei.…”

Section: Introductionmentioning

confidence: 99%

Atypical ductal hyperplasia is a multipotent precursor of breast carcinoma

Kader

Hill

Zethoven

et al. 2019

The Journal of Pathology

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The current model for breast cancer progression proposes independent ‘low grade (LG)‐like’ and ‘high grade (HG)‐like’ pathways but lacks a known precursor to HG cancer. We applied low‐coverage whole‐genome sequencing to atypical ductal hyperplasia (ADH) with and without carcinoma to shed light on breast cancer progression. Fourteen out of twenty isolated ADH cases harboured at least one copy number alteration (CNA), but had fewer aberrations than LG or HG ductal carcinoma in situ (DCIS). ADH carried more HG‐like CNA than LG DCIS (e.g. 8q gain). Correspondingly, 64% (7/11) of ADH cases with synchronous HG carcinoma were clonally related, similar to LG carcinoma (67%, 6/9). This study represents a significant shift in our understanding of breast cancer progression, with ADH as a common precursor lesion to the independent ‘low grade‐like’ and ‘high grade‐like’ pathways. These data suggest that ADH can be a precursor of HG breast cancer and that LG and HG carcinomas can evolve from a similar ancestor lesion. We propose that although LG DCIS may be committed to a LG molecular pathway, ADH may remain multipotent, progressing to either LG or HG carcinoma. This multipotent nature suggests that some ADH cases could be more clinically significant than LG DCIS, requiring biomarkers for personalising management. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Atypical ductal hyperplasia: update on diagnosis, management, and molecular landscape

Cited by 52 publications

References 78 publications

Gene expression signature of atypical breast hyperplasia and regulation by SFRP1

Gene expression signature of atypical breast hyperplasia and regulation by SFRP1

The Immune Microenvironment of Breast Cancer Progression

Atypical ductal hyperplasia is a multipotent precursor of breast carcinoma

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