<scp>Mouse‐INtraDuctal</scp> (<scp>MIND</scp>): an <i>in vivo</i> model for studying the underlying mechanisms of <scp>DCIS</scp> malignancy

Yu, Hong; Limback, Darlene; Elsarraj, Hanan S.; Harper, Haleigh; Haines, Haley; Hansford, Hayley; Ricci, Michael A.; Kaufman, Carolyn S.; Wedlock, Emily; Xu, Min; Zhang, Jianhua; May, Lisa; Cusick, Therese; Inciardi, Marc; Redick, Mark; Gatewood, Jason; Winblad, Onalisa; Aripoli, Allison; Huppe, Ashley; Balanoff, Christa; Wagner, Jamie L.; Amin, Amanda L.; Larson, Kelsey E.; Ricci, Lawrence R.; Tawfik, Ossama; Razek, Hana; Meierotto, Ruby O; Madan, Rashna; Godwin, Andrew K.; Thompson, Jeffrey; Hilsenbeck, Susan G.; Futreal, Andy; Thompson, Alastair; Hwang, E. Shelley; Fan, Fang; Behbod, Fariba

doi:10.1002/path.5820

Cited by 14 publications

(9 citation statements)

References 80 publications

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“…MIND Py230 tumors were characterized as having a phenotype more comparable to ‘pushing’ border human breast cancers ( Figure 2 D,F). These data are consistent with previously published work demonstrating that tumors that arise from intraductal human breast cancer cell delivery more closely reflect human breast cancer histology than tumors derived from mammary fat pad injections [ 26 , 27 , 31 ].…”

Section: Resultssupporting

confidence: 92%

“…MIND models permit assessment of early interactions between intraductal cancer cells, normal mammary epithelium, and the myoepithelium, as well as the underlying basement membrane. Previous studies using human breast cancer cell lines demonstrate that intraductal injection results in human tumor cell incorporation into the ductal epithelium [ 20 ], followed by the development of robust DCIS-like lesions with relatively long latency to invasive cancer [ 25 , 29 , 30 , 31 ]. Of note, these MIND models most frequently use invasive human breast cancer cell lines as opposed to pre-cancerous cell lines, yet robustly develop stable DCIS lesions.…”

Section: Introductionmentioning

confidence: 99%

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Isogenic Mammary Models of Intraductal Carcinoma Reveal Progression to Invasiveness in the Absence of a Non-Obligatory In Situ Stage

Bernhardt

Mitchell

Stamnes

et al. 2023

Cancers

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In breast cancer, progression to invasive ductal carcinoma (IDC) involves interactions between immune, myoepithelial, and tumor cells. Development of IDC can proceed through ductal carcinoma in situ (DCIS), a non-obligate, non-invasive stage, or IDC can develop without evidence of DCIS and these cases associate with poorer prognosis. Tractable, immune-competent mouse models are needed to help delineate distinct mechanisms of local tumor cell invasion and prognostic implications. To address these gaps, we delivered murine mammary carcinoma cell lines directly into the main mammary lactiferous duct of immune-competent mice. Using two strains of immune-competent mice (BALB/c, C57BL/6), one immune-compromised (severe combined immunodeficiency; SCID) C57BL/6 strain, and six different murine mammary cancer cell lines (D2.OR, D2A1, 4T1, EMT6, EO771, Py230), we found early loss of ductal myoepithelial cell differentiation markers p63, α-smooth muscle actin, and calponin, and rapid formation of IDC in the absence of DCIS. Rapid IDC formation also occurred in the absence of adaptive immunity. Combined, these studies demonstrate that loss of myoepithelial barrier function does not require an intact immune system, and suggest that these isogenic murine models may prove a useful tool to study IDC in the absence of a non-obligatory DCIS stage—an under-investigated subset of poor prognostic human breast cancer.

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Section: Resultssupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Isogenic Mammary Models of Intraductal Carcinoma Reveal Progression to Invasiveness in the Absence of a Non-Obligatory In Situ Stage

Bernhardt

Mitchell

Stamnes

et al. 2023

Cancers

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“…Previous studies using cell lines such as MCF10DCIS.com and SUM225 or small collections of DCIS xenografts have not led to reliable biomarkers for DCIS progression, mainly because cell lines only model ER − DCIS and because the small number of available xenografts did not account for the heterogeneity of the disease. 13 , 33 , 34 Here, we report the generation of a large biobank of 115 orthotopic DCIS-MIND models recapitulating the molecular and histological heterogeneity of the patient population. 35 , 36 Monitoring of the natural progression of DCIS of our biobank showed that 46% of DCIS cases progress into invasive disease, suggesting that around half of the DCIS lesions in patients would stay indolent if left untreated.…”

Section: Discussionmentioning

confidence: 99%

“… 9 , 10 This method results in DCIS lesions retaining the sample-specific estrogen receptor (ER), progesterone receptor (PR), and HER2 expression, and can be used to follow the progression of DCIS lesions over time. 8 , 11 , 12 , 13 …”

Section: Introductionmentioning

confidence: 99%

A living biobank of patient-derived ductal carcinoma in situ mouse-intraductal xenografts identifies risk factors for invasive progression

Hutten¹,

Bruijn²,

Lutz³

et al. 2023

Cancer Cell

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“… 49 The higher the grade, the higher the risk of invasive breast cancer (IBC), 50 , 51 although the prognostic estimation is not accurate. Recent basic research using lineage tracing, genomics, and transcriptomics has provided evidence that multiple independent clones derived from DCIS evolve into IBC, although the molecular mechanisms of progression from DCIS to IBC remain elusive 52 , 53 (Figure 1 ). Inhibition of DCIS progression to IBC is an important preventive therapeutic strategy against breast cancer.…”

Section: Ductal Carcinoma In Situ (Dcis) and Current Therapies Agains...mentioning

confidence: 99%

Inflammatory cytokine‐enriched microenvironment plays key roles in the development of breast cancers

Takeuchi

Gotoh

2023

Cancer Science

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As the incidence of breast cancer continues to increase, it is critical to develop prevention strategies for this disease. Inflammation underlies the onset of the disease, and NF‐κB is a master transcription factor for inflammation. Nuclear factor‐κB (NF‐κB) is activated in a variety of cell types, including normal epithelial cells, cancer cells, cancer‐associated fibroblasts (CAFs), and immune cells. Ductal carcinoma in situ (DCIS) is the earliest stage of breast cancer, and not all DCIS lesions develop into invasive breast cancers (IBC). Currently, most patients with DCIS undergo surgery with postoperative therapy, although there is a risk of overtreatment. In BRCA mutants, receptor activator of NF‐κB (RANK)‐positive progenitors serve as the cell of origin, and treatment using the RANK monoclonal antibody reduces the risk of IBC. There is still an unmet need to diagnose malignant DCIS, which has the potential to progress to IBC, and to establish appropriate prevention strategies. We recently demonstrated novel molecular mechanisms for NF‐κB activation in premalignant mammary tissues, which include DCIS, and the resultant cytokine‐enriched microenvironment is essential for breast cancer development. On the early endosomes in a few epithelial cells, the adaptor protein FRS2β, forming a complex with ErbB2, carries the IκB kinase (IKK) complex and leads to the activation of NF‐κB, thereby inducing a variety of cytokines. Therefore, the FRS2β‐NFκB axis in the inflammatory premalignant environment could be targetable to prevent IBC. Further analysis of the molecular mechanisms of inflammation in the premalignant microenvironment is necessary to prevent the risk of IBC.

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Mouse‐INtraDuctal (MIND): an in vivo model for studying the underlying mechanisms of DCIS malignancy

Abstract: On behalf of the Grand Challenge PRECISION Consortium'.

Cited by 14 publications

References 80 publications

Isogenic Mammary Models of Intraductal Carcinoma Reveal Progression to Invasiveness in the Absence of a Non-Obligatory In Situ Stage

Isogenic Mammary Models of Intraductal Carcinoma Reveal Progression to Invasiveness in the Absence of a Non-Obligatory In Situ Stage

A living biobank of patient-derived ductal carcinoma in situ mouse-intraductal xenografts identifies risk factors for invasive progression

Inflammatory cytokine‐enriched microenvironment plays key roles in the development of breast cancers

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