title: BAD-mediated apoptotic pathway is associated with human cancer development.
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.
authors: Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors: Xiaomang B
authors: XB
authors: Stickles
authors: Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors: Douglas C
authors: DC
authors: Marchion
authors: Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors: Elona
authors: E
authors: Bicaku
authors: Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors: Entidhar
authors: E
authors: Al Sawah
authors: Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors: Forough
authors: F
authors: Abbasi
authors: Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors: Yin
authors: Y
authors: Xiong
authors: Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors: Nadim
authors: N
authors: Bou Zgheib
authors: Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors: Bernadette M
authors: BM
authors: Boac
authors: Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors: Brian C
authors: BC
authors: Orr
authors: Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors: Patricia L
authors: PL
authors: Judson
authors: Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors: Amy
authors: A
authors: Berry
authors: Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors: Ardeshir
authors: A
authors: Hakam
authors: Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors: Robert M
authors: RM
authors: Wenham
authors: Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors: Sachin M
authors: SM
authors: Apte
authors: Cancer Informatics Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors: Anders E
authors: AE
authors: Berglund
authors: Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors: Johnathan M
authors: JM
authors: Lancaster
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D019610:Cytoprotection; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D009369:Neoplasms / Q000209:etiology* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D000071636:Protein Phosphatase 2C; D015398:Signal Transduction; D051025:bcl-Associated Death Protein / Q000378:metabolism*
chemical_list: D051025:bcl-Associated Death Protein; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C
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