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BAD-mediated apoptotic pathway is associated with human cancer development.

Stickles XB, Marchion DC, Bicaku E, Al Sawah E, Abbasi F, Xiong Y, Bou Zgheib N, Boac BM, Orr BC, Judson PL, Berry A, Hakam A, Wenham RM, Apte SM, Berglund AE, Lancaster JM - Int. J. Mol. Med. (2015)

Bottom Line: The malignant transformation of normal cells is caused in part by aberrant gene expression disrupting the regulation of cell proliferation, apoptosis, senescence and DNA repair.The expression of the BAD-mediated apoptotic pathway phosphatase, PP2C, was evaluated by RT-qPCR in the normal and ovarian cancer tissue samples.The BAD-mediated apoptotic pathway is thus associated with the development of human cancers likely influenced by the protein levels of pBAD.

View Article: PubMed Central - PubMed

Affiliation: Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.

ABSTRACT
The malignant transformation of normal cells is caused in part by aberrant gene expression disrupting the regulation of cell proliferation, apoptosis, senescence and DNA repair. Evidence suggests that the Bcl-2 antagonist of cell death (BAD)-mediated apoptotic pathway influences cancer chemoresistance. In the present study, we explored the role of the BAD-mediated apoptotic pathway in the development and progression of cancer. Using principal component analysis to derive a numeric score representing pathway expression, we evaluated clinico-genomic datasets (n=427) from corresponding normal, pre-invasive and invasive cancers of different types, such as ovarian, endometrial, breast and colon cancers in order to determine the associations between the BAD-mediated apoptotic pathway and cancer development. Immunofluorescence was used to compare the expression levels of phosphorylated BAD [pBAD (serine-112, -136 and -155)] in immortalized normal and invasive ovarian, colon and breast cancer cells. The expression of the BAD-mediated apoptotic pathway phosphatase, PP2C, was evaluated by RT-qPCR in the normal and ovarian cancer tissue samples. The growth-promoting effects of pBAD protein levels in the immortalized normal and cancer cells were assessed using siRNA depletion experiments with MTS assays. The expression of the BAD-mediated apoptotic pathway was associated with the development and/or progression of ovarian (n=106, p<0.001), breast (n=185, p<0.0008; n=61, p=0.04), colon (n=22, p<0.001) and endometrial (n=33, p<0.001) cancers, as well as with ovarian endometriosis (n=20, p<0.001). Higher pBAD protein levels were observed in the cancer cells compared to the immortalized normal cells, whereas PP2C gene expression was lower in the cancer compared to the ovarian tumor tissue samples (n=76, p<0.001). The increased pBAD protein levels after the depletion of PP2C conferred a growth advantage to the immortalized normal and cancer cells. The BAD-mediated apoptotic pathway is thus associated with the development of human cancers likely influenced by the protein levels of pBAD.

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Expression of the BAD-mediated apoptotic pathway is associated with the development and progression of cancer. BAD-mediated apoptotic pathway expression, as modeled by principal component analysis (PCA), was higher in the corresponding normal tissue samples than in the (A) ovarian cancer samples (p<0.001); (B) breast cancer samples (p<0.001); and (C) colon cancer samples (p<0.001). When BAD-mediated apoptotic pathway expression was compared among various stages of cancer progression, the expression score was higher in (D) breast tissue samples, with atypical ductal hyperplasia (ADH) > ductal carcinoma in situ (DCIS) > invasive ductal carcinoma (IDC) (p=0.04); in (E) endometrial cancer tissue samples, with normal > atypical endometrial hyperplasia (AEH) > invasive carcinomas (p<0.001); and in (F) endometriosis tissue samples, with normal > ovarian endometriosis samples (p<0.001).
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f1-ijmm-35-04-1081: Expression of the BAD-mediated apoptotic pathway is associated with the development and progression of cancer. BAD-mediated apoptotic pathway expression, as modeled by principal component analysis (PCA), was higher in the corresponding normal tissue samples than in the (A) ovarian cancer samples (p<0.001); (B) breast cancer samples (p<0.001); and (C) colon cancer samples (p<0.001). When BAD-mediated apoptotic pathway expression was compared among various stages of cancer progression, the expression score was higher in (D) breast tissue samples, with atypical ductal hyperplasia (ADH) > ductal carcinoma in situ (DCIS) > invasive ductal carcinoma (IDC) (p=0.04); in (E) endometrial cancer tissue samples, with normal > atypical endometrial hyperplasia (AEH) > invasive carcinomas (p<0.001); and in (F) endometriosis tissue samples, with normal > ovarian endometriosis samples (p<0.001).

Mentions: In each tissue type examined, the BAD-mediated apoptotic pathway PCA score was higher in the normal tissue than in the corresponding invasive carcinoma samples (Fig. 1). The normal ovary samples (n=28) had a mean BAD-mediated apoptotic pathway expression score of 8.1968, whereas the ovarian cancer samples (n=78) had a mean score of −2.9424 (P<0.001) (Fig. 1A). The normal breast samples (n=143) had a mean BAD-mediated apoptotic pathway expression score of 2.721 vs. a score of −0.799 for the breast cancer samples (n=42; P<0.001) (Fig. 1B). The normal colon samples (n=10) had a mean BAD-mediated apoptotic pathway expression score of 4.049 vs. a value of −3.374 for the colon cancer samples (n=12; P<0.001) (Fig. 1C). When the BAD-mediated apoptotic pathway expression results were compared among the various stages of cancer progression, the expression score was higher in the atypical ductal hyperplasia breast tissue samples (mean expression score, 0.687, n=8) than in the ductal carcinoma in situ samples (mean expression score, 0.046, n=23) and higher in ductal carcinoma in situ than in invasive ductal carcinoma (mean expression score, −0.298, n=30, Spearman’s correlation estimate, −0.264, P=0.04) (Fig. 1D). BAD-mediated apoptotic pathway expression was higher in the normal endometrial samples (mean expression score, 6.745, n=9) than in the hyperplastic tissue samples (mean expression score, 4.161, n=4) and higher in the hyperplastic tissue samples than in the carcinoma samples (mean expression score, −3.867, n=20, Spearman correlation estimate, −0.795, P<0.001) (Fig. 1E). The mean BAD-mediated apoptotic pathway expression score of the normal endometrium samples (n=10) was 5.614 vs. −5.614 in the ovarian endometriosis samples (n=10, P<0.001) (Fig. 1F).


BAD-mediated apoptotic pathway is associated with human cancer development.

Stickles XB, Marchion DC, Bicaku E, Al Sawah E, Abbasi F, Xiong Y, Bou Zgheib N, Boac BM, Orr BC, Judson PL, Berry A, Hakam A, Wenham RM, Apte SM, Berglund AE, Lancaster JM - Int. J. Mol. Med. (2015)

Expression of the BAD-mediated apoptotic pathway is associated with the development and progression of cancer. BAD-mediated apoptotic pathway expression, as modeled by principal component analysis (PCA), was higher in the corresponding normal tissue samples than in the (A) ovarian cancer samples (p<0.001); (B) breast cancer samples (p<0.001); and (C) colon cancer samples (p<0.001). When BAD-mediated apoptotic pathway expression was compared among various stages of cancer progression, the expression score was higher in (D) breast tissue samples, with atypical ductal hyperplasia (ADH) > ductal carcinoma in situ (DCIS) > invasive ductal carcinoma (IDC) (p=0.04); in (E) endometrial cancer tissue samples, with normal > atypical endometrial hyperplasia (AEH) > invasive carcinomas (p<0.001); and in (F) endometriosis tissue samples, with normal > ovarian endometriosis samples (p<0.001).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4356438&req=5

f1-ijmm-35-04-1081: Expression of the BAD-mediated apoptotic pathway is associated with the development and progression of cancer. BAD-mediated apoptotic pathway expression, as modeled by principal component analysis (PCA), was higher in the corresponding normal tissue samples than in the (A) ovarian cancer samples (p<0.001); (B) breast cancer samples (p<0.001); and (C) colon cancer samples (p<0.001). When BAD-mediated apoptotic pathway expression was compared among various stages of cancer progression, the expression score was higher in (D) breast tissue samples, with atypical ductal hyperplasia (ADH) > ductal carcinoma in situ (DCIS) > invasive ductal carcinoma (IDC) (p=0.04); in (E) endometrial cancer tissue samples, with normal > atypical endometrial hyperplasia (AEH) > invasive carcinomas (p<0.001); and in (F) endometriosis tissue samples, with normal > ovarian endometriosis samples (p<0.001).
Mentions: In each tissue type examined, the BAD-mediated apoptotic pathway PCA score was higher in the normal tissue than in the corresponding invasive carcinoma samples (Fig. 1). The normal ovary samples (n=28) had a mean BAD-mediated apoptotic pathway expression score of 8.1968, whereas the ovarian cancer samples (n=78) had a mean score of −2.9424 (P<0.001) (Fig. 1A). The normal breast samples (n=143) had a mean BAD-mediated apoptotic pathway expression score of 2.721 vs. a score of −0.799 for the breast cancer samples (n=42; P<0.001) (Fig. 1B). The normal colon samples (n=10) had a mean BAD-mediated apoptotic pathway expression score of 4.049 vs. a value of −3.374 for the colon cancer samples (n=12; P<0.001) (Fig. 1C). When the BAD-mediated apoptotic pathway expression results were compared among the various stages of cancer progression, the expression score was higher in the atypical ductal hyperplasia breast tissue samples (mean expression score, 0.687, n=8) than in the ductal carcinoma in situ samples (mean expression score, 0.046, n=23) and higher in ductal carcinoma in situ than in invasive ductal carcinoma (mean expression score, −0.298, n=30, Spearman’s correlation estimate, −0.264, P=0.04) (Fig. 1D). BAD-mediated apoptotic pathway expression was higher in the normal endometrial samples (mean expression score, 6.745, n=9) than in the hyperplastic tissue samples (mean expression score, 4.161, n=4) and higher in the hyperplastic tissue samples than in the carcinoma samples (mean expression score, −3.867, n=20, Spearman correlation estimate, −0.795, P<0.001) (Fig. 1E). The mean BAD-mediated apoptotic pathway expression score of the normal endometrium samples (n=10) was 5.614 vs. −5.614 in the ovarian endometriosis samples (n=10, P<0.001) (Fig. 1F).

Bottom Line: The malignant transformation of normal cells is caused in part by aberrant gene expression disrupting the regulation of cell proliferation, apoptosis, senescence and DNA repair.The expression of the BAD-mediated apoptotic pathway phosphatase, PP2C, was evaluated by RT-qPCR in the normal and ovarian cancer tissue samples.The BAD-mediated apoptotic pathway is thus associated with the development of human cancers likely influenced by the protein levels of pBAD.

View Article: PubMed Central - PubMed

Affiliation: Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.

ABSTRACT
The malignant transformation of normal cells is caused in part by aberrant gene expression disrupting the regulation of cell proliferation, apoptosis, senescence and DNA repair. Evidence suggests that the Bcl-2 antagonist of cell death (BAD)-mediated apoptotic pathway influences cancer chemoresistance. In the present study, we explored the role of the BAD-mediated apoptotic pathway in the development and progression of cancer. Using principal component analysis to derive a numeric score representing pathway expression, we evaluated clinico-genomic datasets (n=427) from corresponding normal, pre-invasive and invasive cancers of different types, such as ovarian, endometrial, breast and colon cancers in order to determine the associations between the BAD-mediated apoptotic pathway and cancer development. Immunofluorescence was used to compare the expression levels of phosphorylated BAD [pBAD (serine-112, -136 and -155)] in immortalized normal and invasive ovarian, colon and breast cancer cells. The expression of the BAD-mediated apoptotic pathway phosphatase, PP2C, was evaluated by RT-qPCR in the normal and ovarian cancer tissue samples. The growth-promoting effects of pBAD protein levels in the immortalized normal and cancer cells were assessed using siRNA depletion experiments with MTS assays. The expression of the BAD-mediated apoptotic pathway was associated with the development and/or progression of ovarian (n=106, p<0.001), breast (n=185, p<0.0008; n=61, p=0.04), colon (n=22, p<0.001) and endometrial (n=33, p<0.001) cancers, as well as with ovarian endometriosis (n=20, p<0.001). Higher pBAD protein levels were observed in the cancer cells compared to the immortalized normal cells, whereas PP2C gene expression was lower in the cancer compared to the ovarian tumor tissue samples (n=76, p<0.001). The increased pBAD protein levels after the depletion of PP2C conferred a growth advantage to the immortalized normal and cancer cells. The BAD-mediated apoptotic pathway is thus associated with the development of human cancers likely influenced by the protein levels of pBAD.

Show MeSH
Related in: MedlinePlus