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

Lei, Xiufen; Bandyopadhyay, Abhik; Le, Thy; Sun, LuZhe

doi:10.1038/sj.onc.1205966

Cited by 74 publications

(74 citation statements)

References 56 publications

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“…Similarly, we have found that inhibition of PLD activity in MDA-MB-231 cells leads to apoptosis (Zhong et al, 2003). Thus, the elevated PLD activity in the MDA-MB-231 cells may potentiate a weak PI3K/Akt signal in these cells, which have functional PTEN (Yu et al, 2002;Lei et al, 2002). Consistent with this hypothesis the level of Akt phosphorylation is substantially lower in the MDA-MB-231 cells relative to other breast cancer cell lines (Yu et al, 2002;our unpublished results).…”

Section: Suppression Of Pld Activity In Mda-mb-231 Cells Confers Senssupporting

confidence: 72%

“…It was reported recently that the secretion of TGF b by these cells suppresses PTEN in these cells and increases the level of phosphorylated Akt (Lei et al, 2002). Moreover, inhibition of PI3K in these cells induced apoptosis (Lei et al, 2002). This suggested that the PI3K/Akt survival pathway plays a role in the survival of these cells.…”

Section: Suppression Of Pld Activity In Mda-mb-231 Cells Confers Sensmentioning

confidence: 98%

“…In this regard, it is of importance that the MDA-MB-231 cells still have a functional PTEN. It was reported recently that the secretion of TGF b by these cells suppresses PTEN in these cells and increases the level of phosphorylated Akt (Lei et al, 2002). Moreover, inhibition of PI3K in these cells induced apoptosis (Lei et al, 2002).…”

Section: Suppression Of Pld Activity In Mda-mb-231 Cells Confers Sensmentioning

confidence: 99%

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Phospholipase D confers rapamycin resistance in human breast cancer cells

2003

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mTOR (mammalian target of rapamycin) is a protein kinase that regulates cell cycle progression and cell growth. Rapamycin is a highly specific inhibitor of mTOR in clinical trials for the treatment of breast and other cancers. mTOR signaling was reported to require phosphatidic acid (PA), the metabolic product of phospholipase D (PLD). PLD, like mTOR, has been implicated in survival signaling and the regulation of cell cycle progression. PLD activity is frequently elevated in breast cancer. We have investigated the effect of rapamycin on breast cancer cell lines with different levels of PLD activity. MCF-7 cells, with relatively low levels of PLD activity, were highly sensitive to the growth-arresting effects of rapamycin, whereas MDA-MB-231 cells, with a 10-fold higher PLD activity than MCF-7 cells, were highly resistant to rapamycin. Elevating PLD activity in MCF-7 cells led to rapamycin resistance; and inhibition of PLD activity in MDA-MB-231 cells increased rapamycin sensitivity. Elevated PLD activity in MCF-7 cells also caused rapamycin resistance for S6 kinase phosphorylation and serum-induced Myc expression. These data implicate mTOR as a critical target for survival signals generated by PLD and suggest that PLD levels in breast cancer could be a valuable indicator of the likely efficacy of rapamycin treatment.

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Section: Suppression Of Pld Activity In Mda-mb-231 Cells Confers Senssupporting

confidence: 72%

Section: Suppression Of Pld Activity In Mda-mb-231 Cells Confers Sensmentioning

confidence: 98%

Section: Suppression Of Pld Activity In Mda-mb-231 Cells Confers Sensmentioning

confidence: 99%

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Phospholipase D confers rapamycin resistance in human breast cancer cells

2003

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“…The mechanisms used by other non-gastrointestinal epithelial cell malignancies, however, have been less well characterized and only recently have studies yielded molecular explanations as to how these cancers evade the growth inhibitory properties of this ubiquitous cytokine (Cordenonsi et al, 2003;Seoane et al, 2004). Equally perplexing is that many human cancers are capable of using TGF-b as a growth promoting factor, including enhancement of cell proliferation, invasiveness and the ability of cancer cells to metastasize (Yin et al, 1999;Lei et al, 2002). As a result of its dual function in mediating carcinogenesis, the development of therapeutics that selectively target the growth promoting arm of this pathway has remained a major challenge.…”

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confidence: 99%

Interleukin-1 alpha mediates the growth proliferative effects of transforming growth factor-beta in p21 null MCF-10A human mammary epithelial cells

et al. 2006

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Transforming growth factor-b type 1 (TGF-b) has been implicated as both a tumor suppressor and a tumor promoter in many solid epithelial cancers. We have previously demonstrated that the cyclin dependent kinase (CDK) inhibitor p21 acts as a molecular switch in determining a growth inhibitory versus growth proliferative response to TGF-b in the spontaneously immortalized human mammary epithelial cell line MCF-10A. We now demonstrate that this proliferative effect of TGF-b is mediated through the proinflammatory cytokine, interleukin-1a (IL-1a). Using gene expression array analysis, we identified IL-1a as a cytokine specifically upregulated only in cells lacking p21 and only upon TGF-b stimulation. Cell proliferation assays verified that recombinant IL-1a was capable of inducing a growth proliferative response in p21 null MCF-10A cells, while neutralizing antibodies against IL-1a prevented the growth proliferative effects of TGF-b. Mechanistically, both the CDK and proliferating cell nuclear antigen (PCNA) inhibitory functions of p21 were responsible for preventing TGF-b induced cell proliferation, but only PCNA inhibition by p21 regulated IL-1a gene expression. These studies demonstrate a novel role for IL-1a in mediating a proliferative response to TGF-b signaling, and suggest that therapies directed against IL-1a could abate the growth proliferative effects of TGF-b without compromising its tumor suppressive function.

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“…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. We have previously shown that autocrine TGFβ contributes to the survival of human breast carcinoma MDA-MB-231 cells revealing a potential mechanism by which autocrine TGFβ maintains the malignancy of breast cancer cells [21].…”

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

Cited by 74 publications

References 56 publications

Phospholipase D confers rapamycin resistance in human breast cancer cells

Phospholipase D confers rapamycin resistance in human breast cancer cells

Interleukin-1 alpha mediates the growth proliferative effects of transforming growth factor-beta in p21 null MCF-10A human mammary epithelial cells

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

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