scholarly journals Metastasis-suppressor NME1 controls the invasive switch of breast cancer by regulating MT1-MMP surface clearance

Oncogene ◽  
2021 ◽  
Author(s):  
Catalina Lodillinsky ◽  
Laetitia Fuhrmann ◽  
Marie Irondelle ◽  
Olena Pylypenko ◽  
Xiao-Yan Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Plasma Membrane ◽  
Cancer Progression ◽  
Ductal Carcinoma ◽  
Xenograft Model ◽  
Breast Tumors ◽  
Endocytic Pathway ◽  
Metastasis Suppressor ◽  
Breast Cancers

AbstractMembrane Type 1 Matrix Metalloprotease (MT1-MMP) contributes to the invasive progression of breast cancers by degrading extracellular matrix tissues. Nucleoside diphosphate kinase, NME1/NM23-H1, has been identified as a metastasis suppressor; however, its contribution to local invasion in breast cancer is not known. Here, we report that NME1 is up-regulated in ductal carcinoma in situ (DCIS) as compared to normal breast epithelial tissues. NME1 levels drop in microinvasive and invasive components of breast tumor cells relative to synchronous DCIS foci. We find a strong anti-correlation between NME1 and plasma membrane MT1-MMP levels in the invasive components of breast tumors, particularly in aggressive histological grade III and triple-negative breast cancers. Knockout of NME1 accelerates the invasive transition of breast tumors in the intraductal xenograft model. At the mechanistic level, we find that MT1-MMP, NME1 and dynamin-2, a GTPase known to require GTP production by NME1 for its membrane fission activity in the endocytic pathway, interact in clathrin-coated vesicles at the plasma membrane. Loss of NME1 function increases MT1-MMP surface levels by inhibiting endocytic clearance. As a consequence, the ECM degradation and invasive potentials of breast cancer cells are enhanced. This study identifies the down-modulation of NME1 as a potent driver of the in situ-to invasive transition during breast cancer progression.

scholarly journals Transcriptome and genome evolution during HER2-amplified breast neoplasia

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Peipei Lu ◽  
Joseph Foley ◽  
Chunfang Zhu ◽  
Katherine McNamara ◽  
Korsuk Sirinukunwattana ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Ductal Carcinoma ◽  
Copy Number Variations ◽  
Neoplastic Progression ◽  
Interferon Signaling ◽  
Her2 Amplification ◽  
Cancer Multiple ◽  
Spatially Oriented

Abstract Background The acquisition of oncogenic drivers is a critical feature of cancer progression. For some carcinomas, it is clear that certain genetic drivers occur early in neoplasia and others late. Why these drivers are selected and how these changes alter the neoplasia’s fitness is less understood. Methods Here we use spatially oriented genomic approaches to identify transcriptomic and genetic changes at the single-duct level within precursor neoplasia associated with invasive breast cancer. We study HER2 amplification in ductal carcinoma in situ (DCIS) as an event that can be both quantified and spatially located via fluorescence in situ hybridization (FISH) and immunohistochemistry on fixed paraffin-embedded tissue. Results By combining the HER2-FISH with the laser capture microdissection (LCM) Smart-3SEQ method, we found that HER2 amplification in DCIS alters the transcriptomic profiles and increases diversity of copy number variations (CNVs). Particularly, interferon signaling pathway is activated by HER2 amplification in DCIS, which may provide a prolonged interferon signaling activation in HER2-positive breast cancer. Multiple subclones of HER2-amplified DCIS with distinct CNV profiles are observed, suggesting that multiple events occurred for the acquisition of HER2 amplification. Notably, DCIS acquires key transcriptomic changes and CNV events prior to HER2 amplification, suggesting that pre-amplified DCIS may create a cellular state primed to gain HER2 amplification for growth advantage. Conclusion By using genomic methods that are spatially oriented, this study identifies several features that appear to generate insights into neoplastic progression in precancer lesions at a single-duct level.

scholarly journals Cumulative Risk Distribution for Interval Invasive Second Breast Cancers After Negative Surveillance Mammography

2018 ◽  
Vol 36 (20) ◽  
pp. 2070-2077 ◽  
Author(s):  
Janie M. Lee ◽  
Linn Abraham ◽  
Diana L. Lam ◽  
Diana S.M. Buist ◽  
Karla Kerlikowske ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Risk ◽  
Primary Breast Cancer ◽  
Carcinoma In Situ ◽  
Ductal Carcinoma ◽  
Interval Cancer ◽  
Invasive Cancer ◽  
Breast Cancers ◽  
Surveillance Mammography

Purpose The aim of the current study was to characterize the risk of interval invasive second breast cancers within 5 years of primary breast cancer treatment. Methods We examined 65,084 surveillance mammograms from 18,366 women with a primary breast cancer diagnosis of unilateral ductal carcinoma in situ or stage I to III invasive breast carcinoma performed from 1996 to 2012 in the Breast Cancer Surveillance Consortium. Interval invasive breast cancer was defined as ipsilateral or contralateral cancer diagnosed within 1 year after a negative surveillance mammogram. Discrete-time survival models—adjusted for all covariates—were used to estimate the probability of interval invasive cancer, given the risk factors for each surveillance round, and aggregated across rounds to estimate the 5-year cumulative probability of interval invasive cancer. Results We observed 474 surveillance-detected cancers—334 invasive and 140 ductal carcinoma in situ—and 186 interval invasive cancers which yielded a cancer detection rate of 7.3 per 1,000 examinations (95% CI, 6.6 to 8.0) and an interval invasive cancer rate of 2.9 per 1,000 examinations (95% CI, 2.5 to 3.3). Median cumulative 5-year interval cancer risk was 1.4% (interquartile range, 0.8% to 2.3%; 10th to 90th percentile range, 0.5% to 3.7%), and 15% of women had ≥ 3% 5-year interval invasive cancer risk. Cumulative 5-year interval cancer risk was highest for women with estrogen receptor– and progesterone receptor–negative primary breast cancer (2.6%; 95% CI, 1.7% to 3.5%), interval cancer presentation at primary diagnosis (2.2%; 95% CI, 1.5% to 2.9%), and breast conservation without radiation (1.8%; 95% CI, 1.1% to 2.4%). Conclusion Risk of interval invasive second breast cancer varies across women and is influenced by characteristics that can be measured at initial diagnosis, treatment, and imaging. Risk prediction models that evaluate the risk of cancers not detected by surveillance mammography should be developed to inform discussions of tailored surveillance.

Ductal Carcinoma In Situ: Challenges, Opportunities, and Uncharted Waters

2012 ◽  
pp. 40-44 ◽  
Author(s):  
Abigail W. Hoffman ◽  
Catherine Ibarra-Drendall ◽  
Virginia Espina ◽  
Lance Liotta ◽  
Victoria Seewaldt
Keyword(s):  
Breast Cancer ◽  
Local Recurrence ◽  
Ductal Carcinoma In Situ ◽  
Carcinoma In Situ ◽  
Ductal Carcinoma ◽  
The United States ◽  
Targeted Prevention ◽  
Breast Cancers ◽  
Increased Risk

Overview: Ductal carcinoma in situ (DCIS) is a heterogeneous group of diseases that differ in biology and clinical behavior. Until 1980, DCIS represented less than 1% of all breast cancer cases. With the increased utilization of mammography, DCIS now accounts for 15% to 25% of newly diagnosed breast cancer cases in the United States. Although our ability to detect DCIS has radically improved, our understanding of the pathophysiology and factors involved in its progression to invasive carcinoma is still poorly defined. In many patients, DCIS will never progress to invasive breast cancer and these women are overtreated. In contrast, some DCIS cases are clinically aggressive and the women may be undertreated. We are able to define some of the predictors of aggressive DCIS compared with DCIS of low malignant potential. However, our ability to risk-stratify DCIS is still in its infancy. Clinical risk factors that predict aggressive disease and increased risk of local recurrence include young age at diagnosis, large lesion size, high nuclear grade, comedo necrosis, and involved margins. Treatment factors such as wider surgical margins and radiation therapy reduce the risk of local recurrence. DCIS represents a key intermediate in the stepwise progression to malignancy, but not all aggressive breast cancers appear to have a DCIS intermediate, notably within triple-negative breast cancer. Ongoing studies of the genetic and epigenetic alterations in precancerous breast lesions (atypia and DCIS) as well as the breast microenvironment are important for developing effective early detection and individualized targeted prevention.

Overdiagnosis and Overtreatment of Breast Cancer

2012 ◽  
pp. e40-e45
Author(s):  
Michael Alvarado ◽  
Elissa Ozanne ◽  
Laura Esserman
Keyword(s):  
Breast Cancer ◽  
Lower Risk ◽  
Ductal Carcinoma ◽  
Early Stage ◽  
Invasive Cancer ◽  
Molecular Testing ◽  
Low Grade ◽  
Breast Cancers ◽  
Molecular Tests

Overview: Breast cancer is the most common cancer in women. Through greater awareness, mammographic screening, and aggressive biopsy of calcifications, the proportion of low-grade, early stage cancers and in situ lesions among all breast cancers has risen substantially. The introduction of molecular testing has increased the recognition of lower risk subtypes, and less aggressive treatments are more commonly recommended for these subtypes. Mammographically detected breast cancers are much more likely to have low-risk biology than symptomatic tumors found between screenings (interval cancers) or that present as clinical masses. Recognizing the lower risk associated with these lesions and the ability to confirm the risk with molecular tests should safely enable the use of less aggressive treatments. Importantly, ductal carcinoma in situ (DCIS) lesions, or what have been called stage I cancers, in and of themselves are not life-threatening. In situ lesions have been treated in a manner similar to that of invasive cancer, but there is little evidence to support that this practice has improved mortality. It is also being recognized that DCIS lesions are heterogeneous, and a substantial proportion of them may in fact be precursors of more indolent invasive cancers. Increasing evidence suggests that these lesions are being overtreated. The introduction of molecular tests should be able to help usher in a change in approach to these lesions. Reclassifying these lesions as part of the spectrum of high-risk lesions enables the use of a prevention approach. Learning from the experience with active surveillance in prostate cancer should empower the introduction of new approaches, with a focus on preventing invasive cancer, especially given that there are effective, United States Food and Drug Administration (FDA)-approved breast cancer preventive interventions.

scholarly journals Changes in Invasive Breast Cancer and Ductal Carcinoma In Situ Rates in Relation to the Decline in Hormone Therapy Use

2010 ◽  
Vol 28 (35) ◽  
pp. 5140-5146 ◽  
Author(s):  
Ghada N. Farhat ◽  
Rod Walker ◽  
Diana S.M. Buist ◽  
Tracy Onega ◽  
Karla Kerlikowske
Keyword(s):  
Breast Cancer ◽  
Hormone Therapy ◽  
Ductal Carcinoma In Situ ◽  
Invasive Breast Cancer ◽  
Carcinoma In Situ ◽  
Ductal Carcinoma ◽  
Screening Mammography ◽  
Breast Cancers ◽  
Cancer Rates

Purpose To assess trends in invasive breast cancer and ductal carcinoma in situ (DCIS) incidence in association with changes in hormone therapy (HT) use in regular mammography screeners. Methods We included 2,071,814 screening mammography examinations performed between January 1997 and December 2006 on 696,385 women age 40 to 79 years; 9,586 breast cancers were diagnosed within 12 months of a screening examination. We calculated adjusted annual rates (mammogram level) for prevalent HT use, incident invasive breast cancer (overall and by tumor histology and estrogen receptor [ER] status), and incident DCIS. Results After a precipitous decrease in HT use in 2002, the incidence of invasive breast cancer decreased significantly in 2002 to 2006 among women age 50 to 69 years (Ptrend(2002–2006) = .005) and 70 to 79 years (Ptrend(2002–2006) = .003) but not in women age 40 to 49 years (Ptrend(2002–2006) = .45). DCIS rates significantly decreased in women age 50 to 69 years after 2002 (Ptrend(2002–2006) = .02). Invasive ductal tumors significantly declined in women age 50 to 69 years and 70 to 79 years in 2002 to 2006. In women age 50 to 69 years, invasive lobular and ER-positive cancer rates declined steadily in 2002 to 2005 (Ptrend(2002–2005) = .02 and .03, respectively), but an elevated rate in 2006 rendered the overall trend nonsignificant (Ptrend(2002–2006) = .89 and .91, respectively). Conclusion In parallel to the sharp decline in HT use in women undergoing regular mammography screening, invasive breast cancer rates decreased in women age 50 to 69 and 70 to 79 years after 2002, and DCIS rates decreased in women age 50 to 69 years, consistent with evidence that HT cessation reduces breast cancer risk. However, the decrease in incidence may have started to level off in 2006; this finding has not been uniformly reported in other populations, warranting further investigation.

scholarly journals Transcriptome and Genome Evolution During HER2-amplified Breast Neoplasia

2020 ◽  
Author(s):  
Peipei Lu ◽  
Joseph Foley ◽  
Chunfang Zhu ◽  
Katherine McNamara ◽  
Korsuk Sirinukunwattana ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Ductal Carcinoma ◽  
Copy Number Variations ◽  
Interferon Signaling ◽  
Her2 Amplification ◽  
Her2 Positive ◽  
Critical Feature ◽  
Cancer Multiple

Abstract The acquisition of oncogenic drivers is a critical feature of cancer progression. For some carcinomas, it is clear that certain genetic drivers occur early in neoplasia and others late. Why these drivers are selected and how these changes alter the neoplasia’s fitness is less understood. Here we use spatially oriented genomic approaches to identify transcriptomic and genetic changes at the single duct level within precursor neoplasia associated with invasive breast cancer. We study HER2 amplification in ductal carcinoma in situ (DCIS) as an event that can be both quantified and spatially located via fluorescence in situ hybridization (FISH) and immunohistochemistry on fixed paraffin-embedded tissue. By combining the HER2-FISH with the laser capture microdissection (LCM) Smart-3SEQ method, we found that HER2 amplification in DCIS alters the transcriptomic profiles and increases diversity of copy number variations (CNVs). Particularly, interferon signaling pathway is activated by HER2 amplification in DCIS, which may provide a prolonged interferon signaling activation in HER2-positive breast cancer. Multiple subclones of HER2-amplified DCIS with distinct CNV profiles are observed, suggesting that multiple events occurred for the acquisition of HER2 amplification. Notably, DCIS acquires key transcriptomic changes and CNV events prior to HER2 amplification, suggesting that pre-amplified DCIS may create a cellular state primed to gain HER2 amplification for growth advantage.

scholarly journals Relationship Between Anthropometric Factors and Risk of Second Breast Cancer Among Women With a History of Ductal Carcinoma In Situ

2018 ◽  
Vol 2 (2) ◽  
Author(s):  
Meghan R Flanagan ◽  
Mei-Tzu C Tang ◽  
Michelle L Baglia ◽  
Peggy L Porter ◽  
Kathleen E Malone ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ductal Carcinoma In Situ ◽  
Carcinoma In Situ ◽  
Ductal Carcinoma ◽  
Breast Cancers ◽  
Increased Risk ◽  
History Of ◽  
Second Breast Cancer ◽  
The Impact

AbstractBackgroundWomen with ductal carcinoma in situ (DCIS) have an elevated risk of a second breast cancer, but few data are available regarding the impact of modifiable lifestyle factors on this risk.MethodsIn a population-based case–control patient study of women with a history of DCIS in western Washington diagnosed between 1996 and 2013, 497 patients diagnosed with DCIS and a second ipsilateral or contralateral invasive or in situ breast cancer were enrolled. There were 965 matched control patients with one DCIS diagnosis. Associations between anthropometric factors and risk of an invasive or in situ second breast cancer event were evaluated using conditional logistic regression. Statistical tests were two-sided.ResultsObesity (body mass index [BMI] ≥ 30 kg/m2) at initial DCIS diagnosis was associated with a 1.6-fold (95% confidence interval [CI] = 1.2 to 2.2) increased risk of any second breast cancer and a 2.2-fold increased risk of a contralateral second breast cancer (95% CI = 1.4 to 3.3) compared with normal weight women (BMI < 25 kg/m2). BMI and weight, both at initial DCIS diagnosis and at the time of the second breast cancer diagnosis, were positively associated with risk of any second and second invasive breast cancers (odds ratio = 1.01–1.04, all P ≤ .03).ConclusionsAlthough additional confirmatory studies are needed, obesity appears to be an important contributor to the risk of second breast cancers within the growing population of women with DCIS. This has potential clinical relevance with respect to identifying which women with a history of DCIS may require more careful monitoring and who may benefit from lifestyle modifications.

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