TLE1 corepressor promotes gefitinib resistance in lung cancer A549 cells via E‑cadherin silencing.

As a putative lung specific oncogene, the transducin-like enhancer of split 1 (TLE1) corepressor drives an anti-apoptotic and pro-epithelial-mesenchymal transition (EMT) gene transcriptional programs in human lung adenocarcinoma (LUAD) cells, thereby promoting anoikis resistance and tumor aggressiveness. Through its survival- and EMT-promoting gene regulatory programs, TLE1 may impact drug sensitivity and resistance in lung cancer cells. In the present study, a novel function of TLE1 was uncovered as an inhibitor of the antitumor effects of the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) gefitinib in the human LUAD cell line A549, which exhibits moderate sensitivity to EGFR-TKI.

Downregulation of Bit1 expression promotes growth, anoikis resistance, and transformation of immortalized human bronchial epithelial cells via Erk activation-dependent suppression of E-cadherin.

The mitochondrial Bit1 protein exerts tumor-suppressive function in NSCLC through induction of anoikis and inhibition of EMT. Having this dual tumor suppressive effect, its downregulation in the established human lung adenocarcinoma A549 cell line resulted in potentiation of tumorigenicity and metastasis in vivo. However, the exact role of Bit1 in regulating malignant growth and transformation of human lung epithelial cells, which are origin of most forms of human lung cancers, has not been examined.

TLE1 inhibits anoikis and promotes tumorigenicity in human lung cancer cells through ZEB1-mediated E-cadherin repression.

The Transducin-like enhancer of split 1 (TLE1) corepressor protein is overexpressed in human lung tumors and is a putative lung-specific oncogene. However, the molecular mechanism underlying its oncogenic function remains to be delineated. Here, we report an important role of TLE1 in promoting lung tumorigenesis by a mechanism involving induction of anoikis resistance.

The Anoikis Effector Bit1 Inhibits EMT through Attenuation of TLE1-Mediated Repression of E-Cadherin in Lung Cancer Cells.

The mitochondrial Bcl-2 inhibitor of transcription 1 (Bit1) protein is part of an anoikis-regulating pathway that is selectively dependent on integrins. We previously demonstrated that the caspase-independent apoptotic effector Bit1 exerts tumor suppressive function in lung cancer in part by inhibiting anoikis resistance and anchorage-independent growth in vitro and tumorigenicity in vivo. Herein we show a novel function of Bit1 as an inhibitor cell migration and epithelial-mesenchymal transition (EMT) in the human lung adenocarcinoma A549 cell line.

TLE1 promotes EMT in A549 lung cancer cells through suppression of E-cadherin.

The Groucho transcriptional corepressor TLE1 protein has recently been shown to be a putative lung specific oncogene, but its underlying oncogenic activity in lung cancer has not been fully elucidated. In this report, we investigated whether TLE1 regulates lung cancer aggressiveness using the human lung adenocarcinoma cell line A549 as a model system. Through a combination of genetic approaches, we found that TLE1 potentiates epithelial-to-mesenchymal transition (EMT) in A549 cells in part through suppression of the tumor suppressor gene E-cadherin.

The anoikis effector Bit1 displays tumor suppressive function in lung cancer cells.

The mitochondrial Bit1 (Bcl-2 inhibitor of transcription 1) protein is a part of an apoptotic pathway that is uniquely regulated by integrin-mediated attachment. As an anoikis effector, Bit1 is released into the cytoplasm following loss of cell attachment and induces a caspase-independent form of apoptosis. Considering that anoikis resistance is a critical determinant of transformation, we hypothesized that cancer cells may circumvent the Bit1 apoptotic pathway to attain anchorage-independence and tumorigenic potential.

Bit1 in anoikis resistance and tumor metastasis.

Epithelial cells and most adherent normal cells rely on adhesion-dependent, integrin-mediated survival signals from the extracellular matrix (ECM) to survive. When these cells are deprived of adhesion to the ECM, they undergo a specific form of apoptosis termed "anoikis." In contrast, malignant cells have attained mechanisms to enable them to survive in the absence of adhesion and are considered anchorage-independent.

TLE1 is an anoikis regulator and is downregulated by Bit1 in breast cancer cells.

TLE1 is a Groucho-related transcriptional repressor protein that exerts survival and antiapoptotic function in several cellular systems and has been implicated in the pathogenesis of cancer. In the present study, we found that TLE1 is a regulator of anoikis in normal mammary epithelial and breast carcinoma cells. The induction of apoptosis following loss of cell attachment to the extracellular matrix (anoikis) in untransformed mammary epithelial MCF10A cells was associated with significant downregulation of TLE1 expression.

Metastasis of tumor cells is enhanced by downregulation of Bit1.

Background: Resistance to anoikis, which is defined as apoptosis induced by loss of integrin-mediated cell attachment to the extracellular matrix, is a determinant of tumor progression and metastasis. We have previously identified the mitochondrial Bit1 (Bcl-2 inhibitor of transcription) protein as a novel anoikis effector whose apoptotic function is independent from caspases and is uniquely controlled by integrins. In this report, we examined the possibility that Bit1 is suppressed during tumor progression and that Bit1 downregulation may play a role in tumor metastasis.

Protein kinase D is a positive regulator of Bit1 apoptotic function.

Bit1 (Bcl-2 inhibitor of transcription) is a mitochondrial protein that induces caspase-independent apoptosis upon its release into the cytoplasm. Bit1 is primarily associated with anoikis (cell death induced by detachment from the extracellular matrix), because the apoptotic function of Bit1 is inhibited by integrin-mediated cell attachment but not by many other antiapoptotic treatments. Here, we show that protein kinase D (PKD) regulates Bit1 apoptotic function.

Anti-invasive and antimetastatic activities of ribosomal protein S6 kinase 4 in breast cancer cells.

Purpose: We have previously shown that p90 ribosomal protein S6 kinase 4 (RSK4), an X-linked gene, is highly up-regulated in mammary tumors of MMTV-c-Myc transgenic mice. In this study, we further investigated whether RSK4 inhibits or promotes breast tumor growth and progression.

Experimental Design: Stable overexpression or small interfering RNA-mediated knockdown of RSK4 was done in the MDA-MB-231 cell line.

Anoikis effector Bit1 negatively regulates Erk activity.

Bcl-2 inhibitor of transcription (Bit1) is a mitochondrial protein that functions as a peptidyl-tRNA hydrolase, but, when released into the cytoplasm, it elicits apoptosis. The proapoptotic function is uniquely counteracted by integrin-mediated cell attachment. We generated a conditional KO mouse of the Bit1 gene by using the Cre-LoxP recombination system.

Perspectives on c-Myc, Cyclin D1, and their interaction in cancer formation, progression, and response to chemotherapy.

C-myc is an oncogene that functions both in the stimulation of cell proliferation and in and apoptosis. C-myc elicits its oncogenic activity by causing immortalization, and to a lesser extent the transformation of cells, in addition to several other mechanisms. C-myc may also enhance or reduce the sensitivity of cancer cells to chemotherapy, but how this dual function is controlled is largely unclear.

c-Myc-induced chemosensitization is mediated by suppression of cyclin D1 expression and nuclear factor-kappa B activity in pancreatic cancer cells.

Purpose: Pancreatic cancer is a highly aggressive disease that remains refractory to various chemotherapeutic agents. Because the proto-oncogene c-myc can modulate apoptosis in response to cytotoxic insults and is commonly overexpressed in pancreatic cancer, we investigated the value of c-myc as a potential modulator of cellular response to various chemotherapeutic agents.

Experimental Design: Stable overexpression or small interfering RNA (siRNA)-mediated knockdown of c-myc and restoration of cyclin D1 were done in the Ela-myc pancreatic tumor cell line.

Synergistic effect of cyclin D1 and c-Myc leads to more aggressive and invasive mammary tumors in severe combined immunodeficient mice.

Cyclin D1 is one of the most commonly overexpressed oncogenes in breast cancer; yet, it is not clear whether cyclin D1 alone is capable of causing malignant transformation of mammary epithelial cells. Here, we show that ectopic expression of cyclin D1 in benign mouse mammary epithelial cells promotes cell proliferation, anchorage-independent growth in soft agar, and tumorigenesis in severe combined immunodeficient mice. To address the possible interaction of cyclin D1 and c-myc in malignant transformation, we used cyclin D1/c-myc dual-expressing clones, which displayed more aggressive and invasive phenotype than cyclin D1-expressing clones.

Aberrant expression of X-linked genes RbAp46, Rsk4, and Cldn2 in breast cancer.

The consequence of activation status or gain/loss of an X-chromosome in terms of the expression of tumor suppressor genes or oncogenes in breast cancer has not been clearly addressed. In this study, we investigated the activation status of the X-chromosomes in a panel of human breast cancer cell lines, human breast carcinoma, and adjacent mammary tissues and a panel of murine mammary epithelial sublines ranging from low to high invasive potentials. Results show that most human breast cancer cell lines were homozygous, but both benign cell lines were heterozygous for highly polymorphic X-loci (IDS and G6PD).

Maspin retards cell detachment via a novel interaction with the urokinase-type plasminogen activator/urokinase-type plasminogen activator receptor system.

It is well documented that tumor suppressive maspin inhibits tumor cell invasion and extracellular matrix remodeling. Maspin is a cytosolic, cell surface-associated, and secreted protein in the serine protease inhibitor superfamily. Although several molecules have been identified as candidate intracellular maspin targets, the extracellular maspin target(s) remains elusive.

The role of X-linked genes in breast cancer.

While contribution of X chromosome in the susceptibility of prostate and ovarian cancer has been demonstrated, the role of X-linked genes in breast carcinogenesis is not clearly known. This study investigated and compared the X-linked gene expression profiles of MMTV-c-myc transgenic mammary tumor (MT) or MMTV-c-myc/MT-tgf-alpha double transgenic mouse mammary tumor (DT) to lactating mammary gland. cDNA microarray analysis using the Affymetrix system identified 1081 genes localized on the X chromosome with 174 and 194 genes at +/-2-fold change levels in MT and DT samples, respectively.

Overexpression of cyclin D1 promotes tumor cell growth and confers resistance to cisplatin-mediated apoptosis in an elastase-myc transgene-expressing pancreatic tumor cell line.

Purpose: Elevated cyclin D1 in human pancreatic cancer correlates with poor prognosis. Because pancreatic cancer is invariably resistant to chemotherapy, the goal of this study was to examine whether the drug resistance of pancreatic cancer cells is in part attributed to cyclin D1 overexpression.

Experimental Design: Stable overexpression and small interfering RNA (siRNA)--mediated knockdown of cyclin D1 were done in the newly established Ela-myc pancreatic tumor cell line.

Antitumor activity of a homing peptide that targets tumor lymphatics and tumor cells.

LyP-1 is a peptide selected from a phage-displayed peptide library that specifically binds to tumor and endothelial cells of tumor lymphatics in certain tumors. Fluorescein-conjugated LyP-1 and a related peptide, LyP-1b, strongly accumulated in primary MDA-MB-435 breast cancer xenografts and their metastases from i.v.

Maspin expression inhibits osteolysis, tumor growth, and angiogenesis in a model of prostate cancer bone metastasis.

Emerging evidence indicates that tumor-associated proteolytic remodeling of bone matrix may underlie the capacity of tumor cells to colonize and survive in the bone microenvironment. Of particular importance, urokinase-type plasminogen activator (uPA) has been shown to correlate with human prostate cancer (PC) metastasis. The importance of this protease may be related to its ability to initiate a proteolytic cascade, leading to the activation of multiple proteases and growth factors.