Ductal carcinoma in situ: to treat or not to treat, that is the question

Seijen, Maartje van; Lips, Esther H.; Thompson, Alastair; Nik-Zainal, Serena; Futreal, Andrew; Hwang, E. Shelley; Verschuur, Ellen; Lane, Joanna; Jonkers, Jos; Rea, Daniel; Wesseling, Jelle

doi:10.1038/s41416-019-0478-6

Cited by 209 publications

(158 citation statements)

References 84 publications

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“…Both forms of carcinoma in situ, if untreated, increase the risk of developing invasive breast cancer. The coexistence of DCIS and invasive carcinoma within the same lesion suggests that DCIS is a nonobligate precursor of invasive carcinoma of no special type [41 , 42] . Multiple models have been proposed for the evolution of DCIS to invasive carcinoma [42] .…”

Section: Breast Cancer Heterogeneitymentioning

confidence: 99%

“…The coexistence of DCIS and invasive carcinoma within the same lesion suggests that DCIS is a nonobligate precursor of invasive carcinoma of no special type [41 , 42] . Multiple models have been proposed for the evolution of DCIS to invasive carcinoma [42] . The lack of understanding of which DCIS lesion is likely to become invasive is still a significant challenge and heavily associated with patient overtreatment [42] .…”

Section: Breast Cancer Heterogeneitymentioning

confidence: 99%

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Breast cancers, mammary stem cells, and cancer stem cells, characteristics, and hypotheses

Taurin

Alkhalifa

2020

Neoplasia

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Highlights Breast cancer is a complex disease arising from the association and cumulation of multiple genetic alterations and environmental factors likely to alter cellular functions. The implication of stem cells in breast cancer’s origin and development has been debated for many years. Analogies between stem cells and cancer cells can be drawn on many levels. Importantly not all cancer cells are stem cells or exhibit properties similar to stem cells. There is no universal cell surface marker of the breast cancer stem cells, imputable to the diversity of the cell of origin, the heterogeneity and fluidity of the microenvironments, and a plethora of possible mutational events. Breast cancer stem cell targeting should hold a great promise for preventing metastasis, reducing the risk of drug resistance, and decreasing recurrence. However, only a few clinical trials assess the effectiveness of treatments on this specific cancer cell population. Additional considerations for the targeting of breast cancer stem cells need to be given to the tumor microenvironment. It is known to promote self-renewal, plasticity, and resistance to treatments. The fate of breast cancer stem cells is indissociable from its environment.

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Section: Breast Cancer Heterogeneitymentioning

confidence: 99%

Section: Breast Cancer Heterogeneitymentioning

confidence: 99%

Breast cancers, mammary stem cells, and cancer stem cells, characteristics, and hypotheses

Taurin

Alkhalifa

2020

Neoplasia

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“…However, de ning DCIS using a small set of known markers has been di cult [30], mainly because medical research on DCIS is more limited compared to that of IDC. Figure 3A) along with high expression of GSTM1 and PGR ( Figure 3B).…”

Section: Mcf10dcismentioning

confidence: 99%

Molecular and Cellular Characterization of Two Patient-Derived Ductal Carcinoma in Situ (DCIS) Cell Lines, ETCC-006 and ETCC-010

Samson

Dean

2020

Preprint

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Background: Currently it is unclear how in situ breast cancer progresses to invasive disease; therefore, a better understanding of the events that occur during the transition to invasive carcinoma is warranted. Here we have conducted a detailed molecular and cellular characterization of two, patient-derived, ductal carcinoma in situ (DCIS) cell lines, ETCC-006 and ETCC-010. Methods: Human DCIS cell lines, ETCC-006 and ETCC-010, were compared against a panel of cell lines including the immortalized, breast epithelial cell line, MCF10A, breast cancer cell lines, MCF7 and MDA-MB-231, and another DCIS line, MCF10DCIS.com. Cell morphology, hormone and HER2/ERBB2 receptor status, cell proliferation, survival, migration, anchorage-independent growth, indicators of EMT, cell signalling pathways and cell cycle proteins were examined using immunostaining, immunoblots, and quantitative, reverse transcriptase PCR (qRT-PCR), along with clonogenic, wound-closure and soft agar assays. RNA sequencing (RNAseq) was used to provide a transcriptomic profile. Results: ETCC-006 and ETCC-010 cells displayed notable differences to another DCIS cell line, MCF10DCIS.com, in terms of morphology, steroid-receptor/HER status and markers of EMT. The ETCC cell lines lack ER/PR and HER, form colonies in clonogenic assays, have migratory capacity and are capable of anchorage-independent growth. Despite being isogenic, less than 30% of differentially expressed transcripts overlapped between the two lines, with enrichment in receptor tyrosine kinase pathways and DNA replication/cell cycle programs. Conclusions: For the first time, we provide a molecular and cellular characterization of two, patient-derived DCIS cell lines, ETCC-006 and ETCC-010, facilitating future investigations into the molecular basis of DCIS to invasive ductal carcinoma transition.

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“…In the late 1980s female breast cancer diagnoses-still the most common female cancer-increased, but the number of associated deaths since then has continuously declined 1 . This has been widely attributed to improvements in diagnostic technologies and strategies that enable clinicians to detect breast cancer development at its early stages [2][3][4] . A quarter of breast cancers are diagnosed as a ductal carcinoma in situ (DCIS) 5 , which is considered a precancerous stage with abnormal cells confined within the mammary duct. When diagnosed with DCIS, clinicians and patients tend to opt for treatments such as surgery and radiation to prevent transition to the malignant invasive ductal carcinoma (IDC).…”

Section: Introductionmentioning

confidence: 99%

“…However, only 30-40% of DCIS cases are likely to progress into IDC, while the remainder are innocuous 6,7 . Survivorship is as high as 98% 5 , but the preemptive approach has raised concerns over the anxiety and negative impact on patients' lives as well as healthcare costs associated with overdiagnosis and overtreatment 2,3,8 . Without a better understanding of the factors that drive DCIS to transition to IDC, apprehensions about forgoing preemptive treatment will naturally remain.…”

Section: Introductionmentioning

confidence: 99%

An Organotypic Mammary Duct Model Capturing Distinct Events of DCIS Progression

Kulwatno

Gong

DeVaux

et al. 2020

Preprint

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Ductal carcinoma in situ (DCIS) is a pre-cancerous stage breast cancer, where abnormal cells are contained within the duct, but have not invaded into the surrounding tissue. However, only 30-40% of DCIS cases are likely to progress into an invasive ductal carcinoma (IDC), while the remainder are innocuous. Since little is known about what contributes to the transition from DCIS to IDC, clinicians and patients tend to opt for treatment, leading to concerns of overdiagnosis and overtreatment. In vitro models are currently being used to probe how DCIS transitions into IDC, but many models do not take into consideration the macroscopic tissue architecture and the biomechanical properties of the microenvironment. Here, we developed an organotypic mammary duct model by molding a channel within a collagen matrix and lining it with a basement membrane. By adjusting the concentration of collagen, we effectively modulated the stiffness and morphological properties of the matrix and examined how an assortment of breast cells responded to changing density and stiffness of the matrix. We first validated the model using two established, phenotypically divergent breast cancer cell lines by demonstrating the ability of the cells to either invade (MDA-MB-231) or cluster (MCF7). We then examined how cells of the isogenic MCF10 series—spanning the range from healthy to aggressive—behaved within our model and observed distinct characteristics of breast cancer progression such as hyperplasia and invasion, in response to collagen concentration. Our results show that the model can recapitulate different stages of breast cancer progression and that the MCF10 series is adaptable to physiologically relevant in vitro studies, demonstrating the potential of both the model and cell lines to elucidate key factors that may contribute to understanding the transition from DCIS to IDC.IMPACT STATEMENTThe success of early preventative measures for breast cancer has left patients susceptible to overdiagnosis and overtreatment. Limited knowledge of factors driving an invasive transition has inspired the development of in vitro models that accurately capture this phenomenon. However, current models tend to neglect the macroscopic architecture and biomechanical properties of the mammary duct. Here, we introduce an organotypic model that recapitulates the cylindrical geometry of the tissue and the altered stroma seen in tumor microenvironments. Our model was able to capture distinct features associated with breast cancer progression, demonstrating its potential to uncover novel insights into disease progression.

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Ductal carcinoma in situ: to treat or not to treat, that is the question

Cited by 209 publications

References 84 publications

Breast cancers, mammary stem cells, and cancer stem cells, characteristics, and hypotheses

Breast cancers, mammary stem cells, and cancer stem cells, characteristics, and hypotheses

Molecular and Cellular Characterization of Two Patient-Derived Ductal Carcinoma in Situ (DCIS) Cell Lines, ETCC-006 and ETCC-010

An Organotypic Mammary Duct Model Capturing Distinct Events of DCIS Progression

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