Molecular Definition of Breast Tumor Heterogeneity

Shipitsin, Michail; Campbell, Lauren L.; Argani, Pedram; Weremowicz, Stanislawa; Bloushtain-Qimron, Noga; Yao, Jun; Nikolskaya, Tatiana; Serebryiskaya, Tatiana; Beroukhim, Rameen; Hu, Min; Halushka, Marc K.; Sukumar, Saraswati; Parker, Leroy M.; Anderson, Karen S.; Harris, Lyndsay N.; Garber, Judy E.; Richardson, Andrea L.; Schnitt, Stuart J.; Nikolsky, Yuri; Gelman, Rebecca; Polyák, Kornélia

doi:10.1016/j.ccr.2007.01.013

Cited by 1,222 publications

(1,253 citation statements)

References 56 publications

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“…3). These results appear to be in line with those of the Shipitsin study [20], where they could identify subsets of genes in their signature that could be correlated with outcome, but were unable to show that their signature as a whole was prognostic. This lack of significance could perhaps be attributed to the low numbers of patients with claudin-low subtype tumors in the van de Vijver data set, as previously noted [22].…”

Section: Gene Signatures Of Ticssupporting

confidence: 77%

“…Other groups in addition to ours have proposed gene transcription signatures of TICs. One gene signature by Liu et al [19] consisted of a set of 186 transcripts (representing 172 unique genes) found differentially expressed between xenograft-or pleural effusionderived CD44 + /CD24 -/low cancer cells and normal breast cells; another signature by Shipitsin et al [20] consisted of a set of 906 genes found differentially expressed between CD44+ cells and CD24+ cells, both obtained from metastatic breast carcinomas.…”

Section: Gene Signatures Of Ticsmentioning

confidence: 99%

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Epithelial-Mesenchymal Transition (EMT) in Tumor-Initiating Cells and Its Clinical Implications in Breast Cancer

Creighton

Chang‐Claude

Rosen

2010

J Mammary Gland Biol Neoplasia

231

189

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There is increasing support for the hypothesis that most tumors contain a subpopulation of cells, referred to here as tumor initiating cells (TICs), with the ability to self-renew and to regenerate all the cell types within the tumor. TICs are enriched in breast cancer patients after common treatments, indicating their intrinsic therapeutic resistance. Two independently-derived gene transcription "signatures" of TICs from different studies indicate enrichment of TICs within the recently-identified "claudin-low" intrinsic molecular subtype of breast cancer. These are characterized by high expression of markers associated with epithelial-mesenchymal transition (EMT), suggesting that claudin-low cells may arise from more immature stem or progenitor cells than other breast cancers. EMT is a process by which cells acquire molecular alterations that facilitate dysfunctional cell-cell adhesive interactions and junctions, as well as a more spindle-shaped morphology. These processes may promote cancer cell progression and invasion into the surrounding microenvironment. Induction of EMT in immortalized human mammary epithelial cells results in an increased ability to form mammospheres, and in the expression of stem cell and TIC markers, suggesting that there may be a direct link between the EMT and the gain of TIC properties. Targeting specific molecular pathways-such as Notch, Wnt, and TGFß-associated with development and EMT in the TIC subpopulation, in addition to conventional chemo-and radiation therapies that target the bulk tumor, may ultimately provide a more effective strategy in treating breast cancer. Here, we review recent evidence of the involvement of EMT in breast cancer TICs, focusing on clinical studies.

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Section: Gene Signatures Of Ticssupporting

confidence: 77%

Section: Gene Signatures Of Ticsmentioning

confidence: 99%

Epithelial-Mesenchymal Transition (EMT) in Tumor-Initiating Cells and Its Clinical Implications in Breast Cancer

Creighton

Chang‐Claude

Rosen

2010

J Mammary Gland Biol Neoplasia

231

189

View full text Add to dashboard Cite

show abstract

“…, 2005), and has also been seen in animal models (Gallahan and Callahan, 1997;Dievart et al, 1999;Callahan and Egan, 2004;Hu et al, 2006). Overexpression of active forms of murine Notch 1-4 The gene expression profile of CD44 þ immunosorted cells was obtained from a published study (Shipitsin et al, 2007). The gene expression profile of CD44 þ mammospheres/neurospheres was obtained from a published study (Dontu et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…The gene expression profile of the MARY-X spheroids was compared with the published gene expression profile of acknowledged models of mammary gland stem cells: CD44 þ mammospheres/neurospheres and CD44 þ immunosorted cells (Dontu et al, 2003;Shipitsin et al, 2007). Several genes in common, including Notch 3 (Sansone et al, 2007a, b), were overexpressed in all three models (Table 3).…”

Section: Notch 3 Dependency Of Ibc Embolus Y Xiao Et Almentioning

confidence: 99%

The lymphovascular embolus of inflammatory breast cancer exhibits a Notch 3 addiction

Xiao

Zou

et al. 2010

Oncogene

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“…When acute myeloid leukemia patients are re-examined after chemotherapy, the persistence of CD34 þ CD38 À cells (proposed to be LICs) predicts a high risk of relapse (van Rhenen et al, 2005). Similarly, the presence of stemness markers within the tumor cells of melanoma and breast cancer patients (ABCB5 þ and CD44 þ , respectively) correlates with a higher rate of cancer progression and poor prognosis (Shipitsin et al, 2007;Schatton et al, 2008). As highlighted above, the eradication of LICs in APL upon treatment with retinoic acid and arsenic supports the concept that agents targeting TICs will lead to complete cure.…”

Section: Novel Paradigms For Cancer Therapy V Pavet Et Almentioning

confidence: 99%

Towards novel paradigms for cancer therapy

et al. 2010

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Cancer is a complex progressive multistep disorder that results from the accumulation of genetic and epigenetic abnormalities, which lead to the transformation of normal cells into malignant derivatives. Despite enormous progress in the understanding of cancer biology including the decryption of multiple regulatory networks governing cell growth and death, and despite the possibility of analyzing (epi)genetic deregulation at the genome-wide scale, cancertargeted therapy is still the exception. In fact, to date there are still far too few examples of therapies leading to cure; treatment-derived toxicity is a major issue, and cancer remains to be one of the largest causes of death worldwide. The purpose of this review is to discuss the state of the art of cancer therapy with respect to the key issue of any treatment, namely its target selectivity. Therefore, we recapitulate and discuss current concepts and therapies targeting tumorspecific features, including oncofusion proteins, aberrant kinase activities and epigenetic tumor makeup. We analyze strategies designed to induce tumor-selective death such as the use of oncolytic virus, tumoricidal proteins (NS1, Eorf4, apoptin, HAMLET (human a-lactalbumin made lethal to tumor cells)) and activation of signaling pathways involved in tumor surveillance. We emphasize the potential of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway, an essential component of the evolutionary developed defense systems that eradicate malignant cells. Finally, we discuss the necessity of targeting tumor-initiating cells (TICs) to avoid relapse and increase the chances of complete remission, and describe emerging concepts that might provide novel avenues for cancer therapy.

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Molecular Definition of Breast Tumor Heterogeneity

Cited by 1,222 publications

References 56 publications

Epithelial-Mesenchymal Transition (EMT) in Tumor-Initiating Cells and Its Clinical Implications in Breast Cancer

Epithelial-Mesenchymal Transition (EMT) in Tumor-Initiating Cells and Its Clinical Implications in Breast Cancer

The lymphovascular embolus of inflammatory breast cancer exhibits a Notch 3 addiction

Towards novel paradigms for cancer therapy

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