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Paired-like Homeodomain Transcription factor 2 expression by breast cancer bone marrow disseminated tumor cells is associated with early recurrent disease development.

Pillai SG, Dasgupta N, Siddappa CM, Watson MA, Fleming T, Trinkaus K, Aft R - Breast Cancer Res. Treat. (2015)

Bottom Line: Suppression of PITX2 expression significantly reduced invasiveness in MDAMB231 cells.Three genes-NKD1, LEF1, and DKK4-were significantly downregulated in response to PITX2 suppression.Furthermore, PITX2 likely plays a role in the metastatic process through its effect on the expression of genes associated with the Wnt/beta-Catenin signaling pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO, 63110, USA.

ABSTRACT
The presence of disseminated tumor cells (DTCs) in the bone marrow (BM) of breast cancer patients is prognostic for early relapse. In the present study, we analyzed the gene expression profiles from BM cells of breast cancer patients to identify molecular signatures associated with DTCs and their relevance to metastatic outcome. We analyzed BM from 30 patients with stage II/III breast cancer by gene expression profiling and correlated expression with metastatic disease development. A candidate gene, PITX2, was analyzed for expression and phenotype in breast cancer cell lines. PITX2 was knocked down in the MDAMB231 cell lines for gene expression analysis and cell invasiveness. Expression of various signaling pathway molecules was confirmed by RT-PCR. We found that the expression of Paired-like Homeobox Transcription factor-2 (PITX2) is absent in the BM of normal healthy volunteers and, when detected in the BM of breast cancer patients, is significantly correlated with early metastatic disease development (p = 0.0062). Suppression of PITX2 expression significantly reduced invasiveness in MDAMB231 cells. Three genes-NKD1, LEF1, and DKK4-were significantly downregulated in response to PITX2 suppression. Expression of PITX2 in BM of early-stage breast cancer patients is associated with risk for early disease recurrence. Furthermore, PITX2 likely plays a role in the metastatic process through its effect on the expression of genes associated with the Wnt/beta-Catenin signaling pathway.

No MeSH data available.


Related in: MedlinePlus

Relative expression pattern of PITX2 isoforms in breast cancer cell lines by qRT–PCR. Expression of each isoform relative to four normal human BM samples
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Fig2: Relative expression pattern of PITX2 isoforms in breast cancer cell lines by qRT–PCR. Expression of each isoform relative to four normal human BM samples

Mentions: Since PITX2 was not expressed in the normal BM and its expression in BM from stage II/III breast cancer patients significantly correlated with early recurrent disease development, we sought to determine the expression levels and physiological function in established breast cancer cell lines. PITX2 has 3 isoforms (Fig. 1). The expression of each isoform in six breast cancer cell lines with varying metastatic potential was determined by qRT–PCR. The highly metastatic breast cancer cell line MDAMB231 expressed all three isoforms of PITX2 at different relative levels. Isoform 1 was fourfold higher in MDAMB 231 than in the next highest PITX2 expressing cell line, CA1A. In this cell line, which is also can form metastases [21] [12], only isoform 1 was detected. The expression of all isoforms of PITX2 in MCF10A and ZR75, both of which are non-invasive, was very low to undetectable. MCF-7 and T47D, both of which are non-metastatic, expressed isoform 3. The two invasive cells lines tested expressed high levels of isoform 1, which has been reported to be important in the Wnt/beta-catenin pathway while the non-invasive cell lines expressed either no/low levels of PITX2 or isoform 3, which is in the TGF-beta pathway. The relative level of expression of the 3 isoforms of PITX2 in cell lines is shown in Fig. 2.Fig. 1


Paired-like Homeodomain Transcription factor 2 expression by breast cancer bone marrow disseminated tumor cells is associated with early recurrent disease development.

Pillai SG, Dasgupta N, Siddappa CM, Watson MA, Fleming T, Trinkaus K, Aft R - Breast Cancer Res. Treat. (2015)

Relative expression pattern of PITX2 isoforms in breast cancer cell lines by qRT–PCR. Expression of each isoform relative to four normal human BM samples
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4589549&req=5

Fig2: Relative expression pattern of PITX2 isoforms in breast cancer cell lines by qRT–PCR. Expression of each isoform relative to four normal human BM samples
Mentions: Since PITX2 was not expressed in the normal BM and its expression in BM from stage II/III breast cancer patients significantly correlated with early recurrent disease development, we sought to determine the expression levels and physiological function in established breast cancer cell lines. PITX2 has 3 isoforms (Fig. 1). The expression of each isoform in six breast cancer cell lines with varying metastatic potential was determined by qRT–PCR. The highly metastatic breast cancer cell line MDAMB231 expressed all three isoforms of PITX2 at different relative levels. Isoform 1 was fourfold higher in MDAMB 231 than in the next highest PITX2 expressing cell line, CA1A. In this cell line, which is also can form metastases [21] [12], only isoform 1 was detected. The expression of all isoforms of PITX2 in MCF10A and ZR75, both of which are non-invasive, was very low to undetectable. MCF-7 and T47D, both of which are non-metastatic, expressed isoform 3. The two invasive cells lines tested expressed high levels of isoform 1, which has been reported to be important in the Wnt/beta-catenin pathway while the non-invasive cell lines expressed either no/low levels of PITX2 or isoform 3, which is in the TGF-beta pathway. The relative level of expression of the 3 isoforms of PITX2 in cell lines is shown in Fig. 2.Fig. 1

Bottom Line: Suppression of PITX2 expression significantly reduced invasiveness in MDAMB231 cells.Three genes-NKD1, LEF1, and DKK4-were significantly downregulated in response to PITX2 suppression.Furthermore, PITX2 likely plays a role in the metastatic process through its effect on the expression of genes associated with the Wnt/beta-Catenin signaling pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO, 63110, USA.

ABSTRACT
The presence of disseminated tumor cells (DTCs) in the bone marrow (BM) of breast cancer patients is prognostic for early relapse. In the present study, we analyzed the gene expression profiles from BM cells of breast cancer patients to identify molecular signatures associated with DTCs and their relevance to metastatic outcome. We analyzed BM from 30 patients with stage II/III breast cancer by gene expression profiling and correlated expression with metastatic disease development. A candidate gene, PITX2, was analyzed for expression and phenotype in breast cancer cell lines. PITX2 was knocked down in the MDAMB231 cell lines for gene expression analysis and cell invasiveness. Expression of various signaling pathway molecules was confirmed by RT-PCR. We found that the expression of Paired-like Homeobox Transcription factor-2 (PITX2) is absent in the BM of normal healthy volunteers and, when detected in the BM of breast cancer patients, is significantly correlated with early metastatic disease development (p = 0.0062). Suppression of PITX2 expression significantly reduced invasiveness in MDAMB231 cells. Three genes-NKD1, LEF1, and DKK4-were significantly downregulated in response to PITX2 suppression. Expression of PITX2 in BM of early-stage breast cancer patients is associated with risk for early disease recurrence. Furthermore, PITX2 likely plays a role in the metastatic process through its effect on the expression of genes associated with the Wnt/beta-Catenin signaling pathway.

No MeSH data available.


Related in: MedlinePlus