Differential copy number aberrations in novel candidate genes associated with progression from in situ to invasive ductal carcinoma of the breast

Liao, Shaoxi; Desouki, Mohamed Mokhtar; Gaile, Daniel P.; Shepherd, Lori; Nowak, Norma J.; Conroy, Jeffrey M.; Barry, William T.; Geradts, Joseph

doi:10.1002/gcc.21991

Cited by 38 publications

(52 citation statements)

References 49 publications

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“…For example, ERBB2 overexpression is significantly more frequent in pure DCIS (up to 50%) than invasive breast cancer (5-15%). 12,13 The limited existing genetic data for pure DCIS 9,14 suggests that copy number events are common and likely to reflect biological behaviour, such as likelihood of progression to invasive carcinoma.…”

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confidence: 99%

Copy number analysis of ductal carcinoma in situ with and without recurrence

et al. 2015

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Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive breast cancer and a frequent mammographic finding requiring treatment. Up to 25% of DCIS can recur and half of recurrences are invasive, but there are no reliable biomarkers for recurrence. We hypothesised that copy number aberrations could predict likelihood of recurrence. We analysed a cohort of pure DCIS cases treated only with wide local excision for genome-wide copy number and loss of heterozygosity using Affymetrix OncoScan MIP arrays. Cases included those without recurrence within 7 years (n = 25) and with recurrence between 1 and 5 years after diagnosis (n = 15). Pure DCIS were broadly similar in copy number changes compared with invasive breast cancer, with the consistent exception of a greater frequency of ERBB2 amplification in DCIS. There were no significant differences in age or ER status between the cases with a recurrence vs those without. Overall, the DCIS cases with recurrence had more copy number events than the DCIS without recurrence. The increased copy number appeared non-random with several genomic regions showing an increase in frequency in recurrent cases, including 20q gain, ERBB2 amplification and 15q loss. Copy number changes may provide prognostic information for DCIS recurrence, but validation in additional cohorts is required. Modern Pathology (2015Pathology ( ) 28, 1174Pathology ( -1184 doi:10.1038/modpathol.2015 published online 19 June 2015 Ductal carcinoma in situ (DCIS) is a proliferation of malignant cells within breast ducts without invasion through the basement membrane. A number of lines of evidence demonstrate that DCIS is a non-obligate precursor of invasive breast cancer, including the natural history of untreated DCIS, 1 the high risk of ipsilateral invasive breast cancer after a diagnosis of DCIS and the common clonal genetic events found in DCIS and synchronous or recurrent invasive breast cancer. 2 Prior to population-based screening mammography, DCIS was an unusual finding comprising only 3-5% of all breast neoplasms. Currently,~20% of cases of screen-detected breast neoplasia are DCIS. 3 Standard treatment has become wide local excision of DCIS with or without adjuvant radiotherapy. 4 Recent clinical trials have found that~25% of DCIS treated with local excision only will recur within 15 years, with the greatest risk of recurrence in the first 5 years. 5 Approximately half of the recurrences will be invasive carcinoma, requiring more extensive treatment, and with a possible decrease in disease-specific survival. 6 Radiotherapy reduces the recurrence rate by about 50%, so despite the fact that only small a small proportion of patients will benefit, many clinicians recommend radiotherapy because of the implications of invasive recurrence. The most commonly used predictive models to estimate the recurrence risk with or without radiotherapy include DCIS grade, tumour size, width

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confidence: 99%

Copy number analysis of ductal carcinoma in situ with and without recurrence

et al. 2015

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“…In genetic studies, one nonsynonymous single nucleotide polymorphism in SMRT has been positively associated with breast cancer (23). In addition, amplification of SMRT has been detected in ductal carcinoma in situ, an early breast lesion, whereas deletion of SMRT was more common in advanced cases of mixed ductal carcinoma in situ and invasive carcinomas (24). The presence of a truncation mutation within the SMRT gene also was detected in The Cancer Genome Atlas breast cancer analyses (2).…”

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confidence: 99%

The SMRT Coregulator Enhances Growth of Estrogen Receptor-α-Positive Breast Cancer Cells by Promotion of Cell Cycle Progression and Inhibition of Apoptosis

Blackmore

Karmakar

et al. 2014

Endocrinology

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The SMRT coregulator functions as a dual coactivator and corepressor for estrogen receptor-␣ (ER␣) in a gene-specific manner, and in several studies its elevated expression correlates with poor outcome for breast cancer patients. A specific role of SMRT in breast cancer progression has not been elucidated, but SMRT knock-down limits estradiol-dependent growth of MCF-7 breast cancer cells. In this study, small-interfering RNA (siRNA) and short-hairpin RNA (shRNA) approaches were used to determine the effects of SMRT depletion on growth of ER␣-positive MCF-7 and ZR-75-1 breast cancer cells, as well as the ER␣-negative MDA-MB-231 breast cancer line. Depletion of SMRT inhibited growth of ER␣-positive cells grown in monolayer but had no effect on growth of the ER␣-negative cells. Reduced SMRT levels also negatively impacted the anchorage-independent growth of MCF-7 cells as assessed by soft agar colony formation assays. The observed growth inhibitions were due to a loss of estradiol-induced progression through the G1/S transition of the cell cycle and increased apoptosis in SMRT-depleted compared with control cells. Gene expression analyses indicated that SMRT inhibits apoptosis by a coordinated regulation of genes involved in apoptosis. Functioning as a dual coactivator for anti-apoptotic genes and corepressor for proapoptotic genes, SMRT can limit apoptosis. Together these data indicate that SMRT promotes breast cancer progression through multiple pathways leading to increased proliferation and decreased apoptosis. (Endocrinology 155: 3251-3261, 2014) B reast cancer remains a major health problem in the United States. In 2013, more than 230,000 women will be diagnosed with new cases of breast cancer and nearly 40,000 women are expected to die from their disease (1). Many cancers, including those of the breast, encompass gene mutations, amplifications, or deletions that can be drivers of disease progression (2). The earliest stages of breast cancer are characterized by excessive, unchecked proliferation of the breast epithelium, whereas death is ultimately caused by growth at metastatic sites (3). The majority (70%-75%) of breast cancers express estrogen receptor-␣ (ER␣), and in these tumors it is a major driver of proliferation (4, 5). Circulating estrogens produced by the ovaries and other tissues as well as locally synthesized in breast, bind to and activate ER␣ leading to programs of gene expression that promote breast carcinogenesis (5-7). Treatments to block the activity of this receptor are therefore commonly used for ER␣-positive tumors; these include antiestrogens and aromatase inhibitors that prevent estradiol (E2) synthesis (8, 9). With the reduction of receptor activity, breast cancer cell proliferation and consequently disease progression is inhibited.Upon binding to ligands, ER␣ undergoes a conformational change that enables it to interact with coactivators and corepressors (6). These coregulators exist in large multiprotein complexes that enable them to directly or indirectly remodel chromatin by alte...

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“…Reviews of the literature can be deceptive, since many studies fail to adequately distinguish DCIS with (or in the presence of) invasive carcinoma from cases of pure DCIS (i.e., DCIS in the absence of invasion). Clearly, from both a clinical and molecular perspective, these DCIS entities are likely to represent separate entities, and current evidence would appear to support this (52)(53)(54).…”

Section: Molecular Progression Of Dcis-through a Glass Darklymentioning

confidence: 93%

Ductal Carcinoma In Situ of the Breast: Can Biomarkers Improve Current Management?

2014

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BACKGROUND:Screening for invasive cancer has led to a marked increase in the detection of ductal carcinoma in situ (DCIS). DCIS is, if appropriately managed, a low-risk disease which has a small chance of impacting on patient life expectancy. However, despite significant advances in prognostic marker development in invasive breast cancer, there are no validated diagnostic assays to inform treatment choice for women with DCIS. Therefore we are unable to target effective treatment strategies to women at high risk and avoid overtreatment of women at low risk of progression to invasive breast cancer. Paradoxically, one effect of this uncertainty is undertreatment of some women.CONTENT: We review current practice and research in the field to identify key challenges in the management of DCIS. The impact of clinical research, particularly on the over and undertreatment of women with DCIS is assessed. We note slow progress toward development of diagnostic biomarkers and highlight key opportunities to accelerate advances in this area.SUMMARY: DCIS is a low-risk disease, its incidence is increasing, and current treatment is effective. However, many women are either over-or undertreated. Despite repeated calls for development of diagnostic biomarkers, progress in this area has been slow, reflecting a relative lack of investment of research effort and funding. Given the low event rate in treated patients and the lateness of recurrences, many previous studies have only limited power to identify independent prognostic and predictive biomarkers. However, the potential for such biomarkers to personalize treatment for DCIS is extremely high.

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Differential copy number aberrations in novel candidate genes associated with progression from in situ to invasive ductal carcinoma of the breast

Cited by 38 publications

References 49 publications

Copy number analysis of ductal carcinoma in situ with and without recurrence

Copy number analysis of ductal carcinoma in situ with and without recurrence

The SMRT Coregulator Enhances Growth of Estrogen Receptor-α-Positive Breast Cancer Cells by Promotion of Cell Cycle Progression and Inhibition of Apoptosis

Ductal Carcinoma In Situ of the Breast: Can Biomarkers Improve Current Management?

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