Identification and Testing of a Gene Expression Signature of Invasive Carcinoma Cells within Primary Mammary Tumors

Wang, Weigang; Goswami, Sumanta; Lapidus, Kyle; Wells, Amber L.; Wyckoff, Jeffrey; Singer, Robert H.; Segall, Jeffrey E.; Condeelis, John S.

doi:10.1158/0008-5472.can-04-1136

Cited by 416 publications

(493 citation statements)

References 54 publications

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“…These genes are coordinately regulated in invasive tumour cells during cell migration in vivo, suggesting that the cofilin pathway has a direct role in determining the invasive and metastatic phenotype 10,12,17,18 .…”

Section: Nih Public Accessmentioning

confidence: 99%

“…Insights into the source of the inconsistencies in the literature about how cofilin and LIMK1 affect tumour cell invasion have emerged from the microarray-based expression profiling of invasive tumour cells collected from mammary tumours of rats and mice 10,12 . In these experiments the expression of genes in the invasive subpopulation of tumour cells was compared to that in the average tumour cell isolated from the primary tumour.…”

Section: The Cofilin Pathway In Tumour Invasionmentioning

confidence: 99%

“…Clearly, altering the expression and activity of LIMK1 has major effects on tumour cell motility and invasion. However, the studies on LIMK1, like those on cofilin, do not agree as to the affects of increased LIMK1 expression on tumour invasion, again supporting the need to investigate the output of the cofilin pathway as an essential part of studies in which the activity of either cofilin, LIMK1 or other proteins within the pathway are manipulated.Insights into the source of the inconsistencies in the literature about how cofilin and LIMK1 affect tumour cell invasion have emerged from the microarray-based expression profiling of invasive tumour cells collected from mammary tumours of rats and mice 10,12 . In these experiments the expression of genes in the invasive subpopulation of tumour cells was compared to that in the average tumour cell isolated from the primary tumour.…”

mentioning

confidence: 99%

“…Animals with tumours containing cells in which cofilin pathway activity was suppressed (LIMK1 overexpression) showed decreased invasion and metastasis and were associated with increased survival; whereas tumours derived from cells with increased cofilin pathway activity (LIMK dominant negative) showed increased invasion and metastasis and were associated with decreased survival. Of particular interest was the finding that tumours derived from tumour cells in which cofilin was overexpressed along with LIMK1 had significantly increased invasion in 10 has shown that the cofilin 1 isoform is selectively upregulated in invasive mammary tumour cells in rats.All of the homologues of ADF and cofilin are believed to share a common structure, as shown in this this space-filling model. This model has been based on the findings of three papers [97][98][99] .…”

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The cofilin pathway in breast cancer invasion and metastasis

Wang¹,

2007

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Recent evidence indicates that metastatic capacity is an inherent feature of breast tumours and not a rare, late acquired event. This has led to new models of metastasis. The interpretation of expression-profiling data in the context of these new models has identified the cofilin pathway as a major determinant of metastasis. Recent studies indicate that the overall activity of the cofilin pathway, and not that of any single gene within the pathway, determines the invasive and metastatic phenotype of tumour cells. These results predict that inhibitors directed at the output of the cofilin pathway will have therapeutic benefit in combating metastasis.Tumour cell motility is the hallmark of invasion and an essential step in metastasis 1,2 . The identification of molecular pathways that contribute to tumour cell motility and invasion is essential for understanding how motility is initiated in tumour cells and how the tumour microenvironment contributes to cell migration. The identification of the molecular pathways of tumour cell invasion will provide new diagnostic approaches and targets for the treatment of metastatic cancer. Recent studies using new technologies, including highdensity microarray-based expression profiling, intravital imaging and the collection of invasive tumour cells from live tumours, have started to extend the traditional model of metastasis and supply new diagnostic and therapeutic markers of metastatic disease.According to the traditional model of metastasis, metastases result from a process similar to Darwinian evolution whereby natural selection works on individual tumour cells to select © 2007 Nature Publishing Group Correspondence to: J.C. Condeeli@aecom.yu.edu. Competing interests statementThe authors declare no competing financial interests. for stable genetic changes. The cells so selected are very rare, and the metastatic cells that arise from this progressive selection of stable genetic mutations within the primary tumour cause metastasis late in tumour progression 3 . However, studies of mammary tumours in mice [4][5][6][7] , expression profiling of both whole human breast tumours 8,9 and the invasive subpopulation of tumour cells isolated from rat and mouse mammary tumours [10][11][12] suggest that the metastatic ability of breast tumours is encoded throughout the bulk of the primary tumour, involves transient changes in gene expression and is acquired at much earlier stages of tumour progression than postulated by the traditional model. These results suggest that a Darwinian-like evolution is accompanied by, and may contribute to, microenvironmentinduced transient changes in gene expression that support the invasive and metastatic phenotype. These results have led to new models where the microenvironment initiates the expression of genes that induce cell motility, invasion and metastasis 11,13 . In the 'tumour microenvironment invasion model' it is proposed that oncogenic mutations in tumour cells lead to microenvironments that are potentially encoded throughout the b...

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Section: Nih Public Accessmentioning

confidence: 99%

Section: The Cofilin Pathway In Tumour Invasionmentioning

confidence: 99%

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The cofilin pathway in breast cancer invasion and metastasis

Wang¹,

2007

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“…Data from cell culture models indicate that b1-integrins regulate phenotypic reversal of breast cancer cells in 3D cultures (Weaver et al, 1997;Wang et al, 2002). In addition, increased b1-expression is associated with an invasive signature in primary mammary tumors and with decreased survival in breast cancer (Wang et al, 2004;Yao et al, 2007). Interestingly, recent described tumor suppressor (SCAI) negatively regulates expression of b1-integrin and loss of SCAI in several cancer types results in increased b1-integrin expression and invasion (Brandt et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Mammary-derived growth inhibitor (MDGI) interacts with integrin α-subunits and suppresses integrin activity and invasion

et al. 2010

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The majority of mortality associated with cancer is due to formation of metastases from the primary tumor. Adhesion mediated by different integrin heterodimers has an important role during cell migration and invasion. Protein interactions with the b1-integrin cytoplasmic tail are known to influence integrin affinity for extracellular ligands, but regulating binding partners for the a-subunit cytoplasmic tails have remained elusive. In this study, we show that mammary-derived growth inhibitor (MDGI) (also known as FABP-3 or H-FABP) binds directly to the cytoplasmic tail of integrin a-subunits and its expression inhibits integrin activity. In breast cancer cell lines, MDGI expression correlates with suppression of the active conformation of integrins. This results in reduced integrin adhesion to type I collagen and fibronectin and inhibition of cell migration and invasion. In tissue microarray of 1331 breast cancer patients, patients with MDGI-positive tumors had more favorable 10-year distant disease-free survival compared with patients with MDGI-negative tumors. Our data indicate that MDGI is a novel interacting partner for integrin a-subunits, and its expression modulates integrin activity and suppresses cell invasion in breast cancer patients. Retained MDGI expression is associated with favorable prognosis.

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Comparison of Mortality Among Participants of Women’s Health Initiative Trials With Screening-Detected Breast Cancers vs Interval Breast Cancers

et al. 2020

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IMPORTANCE Interval breast cancers (IBCs) are cancers that emerge after a mammogram with negative results but before the patient's next scheduled screening. Interval breast cancer has a worse prognosis than cancers detected by screening; however, it is unknown whether the length of the interscreening period is associated with prognostic features and mortality.OBJECTIVE To compare the prognostic features and mortality rate of women with IBCs diagnosed within 1 year or between 1 and 2.5 years of a mammogram with negative results with the prognostic features and mortality rate of women with breast cancers detected by screening. DESIGN, SETTING, AND PARTICIPANTSThis cohort study used mammography data, tumor characteristics, and patient demographic data from the Women's Health Initiative study, which recruited participants from 1993 to 1998 and followed up with participants for a median of 19 years. The present study sample for these analyses included women aged 50 to 79 years who participated in the Women's Health Initiative study and includes data collected through March 31, 2018. There were 5455 incidents of breast cancer; only 3019 women compliant with screening were retained in analyses. Statistical analysis was performed from October 25, 2018, to November 24, 2019. Breast cancers detected by screening and IBCs were defined based on mammogram history, date of last mammogram, type of visit, and results of examination. Interval breast cancers were subdivided into those occurring within 1 year or between 1 and 2.5 years after the last protocol-mandated mammogram with negative results. MAIN OUTCOMES AND MEASURESThe primary outcome of this study was breast cancer-specific mortality for each case of breast cancer detected by screening and IBCs detected within 1 year or between 1 and 2.5 years from a mammogram with negative results. Secondary outcomes included prognostic and tumor characteristics for each group. Comparisons between groups were made using the t test, the χ 2 test, and Fine-Gray multivariable cumulative incidence regression analyses. RESULTS Among the 3019 participants in this analysis, all were women with a mean (SD) age of 63.1 (6.8) years at enrollment and 68.5 (7.1) years at diagnosis. A total of 1050 cases of IBC were identified, with 324 (30.9%) diagnosed within 1 year from a mammogram with negative results and 726 (69.1%) diagnosed between 1 and 2.5 years after last mammogram with negative results. The remaining 1969 cases were breast cancers detected by screening. Interval breast cancers diagnosed within 1 year from a mammogram with negative results had significantly more lobular histologic characteristics (13.0% vs. 8.1%), a larger tumor size (1.97 cm vs 1.43 cm), a higher clinical stage (28.4% vs 17.3% regional and 3.7% vs 0.6% distant), and more lymph node involvement (27.1% vs 17.0%) than cancers detected by screening. Unadjusted breast cancer-specific mortality hazard ratios were significantly higher for IBCs diagnosed within 1 year from a mammogram with negative results compared with breast ...

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Identification and Testing of a Gene Expression Signature of Invasive Carcinoma Cells within Primary Mammary Tumors

Cited by 416 publications

References 54 publications

The cofilin pathway in breast cancer invasion and metastasis

The cofilin pathway in breast cancer invasion and metastasis

Mammary-derived growth inhibitor (MDGI) interacts with integrin α-subunits and suppresses integrin activity and invasion

Comparison of Mortality Among Participants of Women’s Health Initiative Trials With Screening-Detected Breast Cancers vs Interval Breast Cancers

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