Analyses of microsatellite instability and the transforming growth factor‐β receptor type II gene mutation in sporadic breast cancer and their correlation with clinicopathological features

Tomita, Shuji; Deguchi, Shigeru; Miyaguni, Takao; Muto, Yoshihiro; Tamamoto, Tohru; Toda, Takayoshi

doi:10.1023/a:1006167210269

Cited by 41 publications

(26 citation statements)

References 16 publications

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“…Thus, these examples most likely represent a "baseline" level of instability rather than the RERϩ phenotype described in colon cancer. These observations are compatible with most reports in the literature, which find some sporadic MSI in microdissected breast cancer, but do not find the high frequency MSI observed in colon cancers with the RERϩ phenotype (Aldaz et al, 1995;Contegiacomo et al, 1995;Dillon et al, 1997;Formantici et al, 1999;Fujii et al, 1998;Gorgoulis et al, 1998;Kasami et al, 1997;Paulson et al, 1996;Rush et al, 1997;Shaw et al, 1996;Sourvinos et al, 1997;Tomita et al, 1999;Toyama et al, 1996;Walsh et al, 1998;Wooster et al, 1994;Yee et al, 1994). One recent study (Anbazhagan et al, 1999) reported no examples of sporadic MSI in a large panel of breast cancers and other studies have observed MSI only rarely (Ͻ5% of cases) (Huiping et al, 1999;Jonsson et al, 1995).…”

Section: Discussionsupporting

confidence: 91%

Genetic Heterogeneity in Ductal Carcinoma of the Breast

Lichy

Dalbègue

Zavar

et al. 2000

Laboratory Investigation

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SUMMARY:Genetic heterogeneity in breast cancer has been observed both by cytogenetic and loss of heterozygosity (LOH) analyses; however, the frequency with which genetically heterogeneous clones arise is unknown. In this study, a panel of 115 breast carcinomas was analyzed to determine the extent of clonal divergence in tumor foci at progressive stages of tumor evolution. Intraductal, infiltrating, and metastatic tumor components were microdissected from each tumor and tested for LOH at 20 microsatellite markers on seven chromosomal arms. Of these cases, 24 (21%) demonstrated genetically divergent clones during tumor progression. Clonal divergence, inferred from discordant LOH patterns, was observed most commonly between intraductal and infiltrating tumor (18 cases), but was also demonstrated between infiltrating and metastatic tumor (11 cases). Discordant LOH was observed with markers on one chromosomal arm in 16 cases, on two in 7 cases, and on four in 1 case, and was observed most commonly with markers on 17p, 17q, and 16q. More detailed microdissection of four cases provided evidence for a specific chronology of genetic alterations occurring during the progression of each tumor. The results indicate that the different tumor components observed microscopically in breast cancer specimens often represent genetically divergent clones. (Lab Invest 2000, 80:291-301).E lucidation of the sequence of genetic events responsible for progression of breast cancer from in situ to infiltrating and metastatic carcinoma is an important goal of efforts to understand the biological basis of this common malignancy. Progression is believed to occur through the accumulation of genetic changes via a process of clonal evolution and clonal selection (Brenner and Aldaz, 1997;Nowell, 1976). Surgically resected breast carcinoma specimens provide a unique resource for analyzing the genetic changes that occur during progression, because specimens typically contain foci of tumor in various stages of progression, including in situ carcinoma, invasive tumor, and lymph node metastases. Morphologically normal epithelial constituents of the breast are usually represented in such specimens, and foci of benign proliferative epithelial lesions may also be present.Detailed studies of colon cancer have shown that adenomatous epithelium adjacent to carcinoma typically has some but not all of the genetic lesions present in the fully developed malignancy, consistent with direct progression from adenoma to carcinoma (Boland et al, 1995;Fearon and Vogelstein, 1990;Vogelstein et al, 1988). By analogy, it might be expected that a similar analysis of breast tumors in different stages of progression would likewise show the accumulation of genetic changes with progression. However, genetic analysis of breast cancer specimens has suggested that the individual foci of tumor identifiable by microscopic examination may not show the precursor-product relationship often observed in colon cancer. Cytogenetic studies in particular have revealed sufficient genetic...

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Section: Discussionsupporting

confidence: 91%

Genetic Heterogeneity in Ductal Carcinoma of the Breast

Lichy

Dalbègue

Zavar

et al. 2000

Laboratory Investigation

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“…For example, Smad4 is frequently mutated or deleted in colon and pancreatic tumors, but not in other tumor types [37]. In breast cancer, mutations of TGFβ RII and Smad4 genes are uncommon [15,16]. Thus, TGFβ pathway appears to be necessary for tumorigenesis and tumor progression in various types of malignancy.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, restoration of autocrine TGFβ signaling in colon carcinoma cells has been shown to inhibit their malignancy [14]. However, several studies showed that complete inactivation of TGFβ signaling through mutations of RII or Smad proteins is rare in many types of cancers including breast cancer [15,16]. In fact, blockade of TGFβ signaling with a dominant negative TGFβ receptor or Smad3 has been shown to inhibit malignant phenotypes in various mammary carcinogenesis models [17][18][19][20] suggesting that autocrine TGFβ signaling is required for breast cancer progression and may be a potential target for cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

Abrogation of TGFβ signaling induces apoptosis through the modulation of MAP kinase pathways in breast cancer cells

Lei

Yang

Nichols

et al. 2007

Experimental Cell Research

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Transforming growth factor beta (TGFβ) can modulate the activity of various MAP kinases. However, how this pathway may mediate TGFβ-induced malignant phenotypes remains elusive. We investigated the role of autocrine TGFβ signaling through MAP kinases in the regulation of cell survival in breast carcinoma MCF-7 cells and untransformed human mammary epithelial cells (HMECs). Our results show that abrogation of autocrine TGFβ signaling with the expression of a dominant negative type II TGFβ receptor (DNRII) or the treatment with a TGFβ type I receptor inhibitor significantly increased apoptosis in MCF-7 cell, but not in HMEC. The expression of DNRII markedly decreased activated/phosphorylated Erk, whereas increased activated/phosphorylated p38 in MCF-7 cells. In contrast, there was no or little change of phosphorylated Erk and p38 in HMECs after the expression of DNRII. Inhibition of Erk activity in MCF-7 control cell induced apoptosis whereas restoration of Erk activity in MCF-7 DNRII cell reduced apoptosis. Similarly, inhibition of p38 activity also inhibited apoptosis in MCF-7 DNRII cell. Thus, autocrine TGFβ signaling can enhance the survival of MCF-7 cells by maintaining the level of active Erk high and the level of active p38 low. Furthermore, the survival properties of TGFβ pathway appear related to transformation supporting the notion that it may be a potential target for cancer therapy.

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“…However, genetic studies have shown that mutational inactivation of TGFb signaling components is restricted to certain subsets of cancer. For example, mutations of TGFb RII and Smad4 are uncommon in breast cancer Tomita et al, 1999). Thus, while various types of cancer cells are often resistant to TGFb's growth inhibitory activity, they retain an otherwise operational autocrine TGFb signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, several studies showed that complete inactivation of TGFb signaling through mutations of RII or Smad proteins is restricted to certain types of cancer and is rare in other types of cancers with or without microsatellite instability. For example, breast, endometrial, pancreatic and lung carcinomas with microsatellite instability showed few or no RII mutation (Abe et al, 1996;Myeroff et al, 1995;Tomita et al, 1999). Similarly, mutations of Smad proteins not including Smad2 and Smad4 were not found in 167 tumors of colon, breast, lung, and pancreas (Riggins et al, 1997), and mutation of Smad4 is uncommon in breast and ovarian carcinomas .…”

Section: Introductionmentioning

confidence: 99%

Autocrine TGFβ supports growth and survival of human breast cancer MDA-MB-231 cells

Lei

Bandyopadhyay

et al. 2002

Oncogene

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Using a cell model system established by ectopic expression of a soluble TGFb type III receptor (sRIII) containing the whole extracellular domain of the type III receptor in human breast cancer MDA-MB-231 cells, we observed that the expression of sRIII antagonized TGFb activity and inhibited both anchorage-dependent and anchorage-independent cell growth. Further studies revealed that sRIII expression induced apoptosis both in vitro and in vivo. Treatment with TGFb neutralizing antibodies or a recombinant human sRIII also induced apoptosis in the MDA-MB-231 parental cells, suggesting that the increased apoptosis after sRIII expression was specifically due to antagonization of autocrine TGFb signaling. Western blotting showed that sRIII clones had a higher PTEN expression level than the control cells did. Treatment with TGFb 1 decreased PTEN and inhibited apoptosis in sRIII cells to a level similar to that in the control cells. sRIII clones also showed a lower level of phosphorylated-Akt than the control cells, consistent with the inhibitory activity of PTEN on Akt activation. Treatment with LY294002, a specific inhibitor of Akt activator, phosphatidylinositol 3-kinase, also induced apoptosis in a dose dependent manner in the control cells. Our results suggest that autocrine TGFb signaling is necessary for the growth and survival of MDA-MB-231 cells.

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Analyses of microsatellite instability and the transforming growth factor‐β receptor type II gene mutation in sporadic breast cancer and their correlation with clinicopathological features

Cited by 41 publications

References 16 publications

Genetic Heterogeneity in Ductal Carcinoma of the Breast

Genetic Heterogeneity in Ductal Carcinoma of the Breast

Abrogation of TGFβ signaling induces apoptosis through the modulation of MAP kinase pathways in breast cancer cells

Autocrine TGFβ supports growth and survival of human breast cancer MDA-MB-231 cells

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