Interaction between APC and Fen1 during breast carcinogenesis

Abstract

Aberrant DNA base excision repair (BER) contributes to malignant transformation. However, inter-individual variations in DNA repair capacity plays a key role in modifying breast cancer risk. We review here emerging evidence that two proteins involved in BER – adenomatous polyposis coli (APC) and flap endonuclease 1 (Fen1) – promote the development of breast cancer through novel mechanisms. APC and Fen1 expression and interaction is increased in breast tumors versus normal cells, APC interacts with and blocks Fen1 activity in Pol-β-directed LP-BER, and abrogation of LP-BER is linked with cigarette smoke condensate-induced transformation of normal breast epithelial cells. Carcinogens increase expression of APC and Fen1 in spontaneously immortalized human breast epithelial cells, human colon cancer cells, and mouse embryonic fibroblasts. Since APC and Fen1 are tumor suppressors, an increase in their levels could protect against carcinogenesis; however, this does not seem to be the case. Elevated Fen1 levels in breast and lung cancer cells may reflect the enhanced proliferation of cancer cells or increased DNA damage in cancer cells compared to normal cells. Inactivation of the tumor suppressor functions of APC and Fen1 is due to their interaction, which may act as a susceptibility factor for breast cancer. The increased interaction of APC and Fen1 may occur due to polypmorphic and/or mutational variation in these genes. Screening of APC and Fen1 polymorphic and/or mutational variations and APC/Fen1 interaction may permit assessment of individual DNA repair capability and the risk for breast cancer development. Such individuals might lower their breast cancer risk by reducing exposure to carcinogens. Stratifying individuals according to susceptibility would greatly assist epidemiologic studies of the impact of suspected environmental carcinogens. Additionally, a mechanistic understanding of the interaction of APC and Fen1 may provide the basis for developing new and effective targeted chemopreventive and chemotherapeutic agents.

The Effect of Cytotoxic Dose of Diclofenac on APC Gene Expression in Cervical Cancer (Hela) Cell Line

“…It has been reported that frequent and long-term use of nonsteroidal anti-inflammatory drugs is associated with decreased odds of cervical cancer [11]. Increase in APC expression level also is associated with decreased risk of cancer [12][13][14][15][16].…”

Whole exome sequencing reveals a combination of rare high and low penetrance variants that correlates with familial breast cancer relative risk

“…This gene encodes a tumor suppressor protein that acts as an antagonist of the Wnt signaling pathway that regulates crucial aspects of cell fate determination, cell migration, cell polarity, neural patterning and organogenesis during embryonic development. This protein can modulate the BER pathway through an interaction with the DNA polymerase β (Pol-β) and the ap endonuclease 1 (Fen-1) and consequently might play an important role in carcinogenesis and chemotherapy by determining whether cells with DNA damage survive or undergo apoptosis 51,52 . In breast tumors, the transcriptional silencing of the APC gene by promoter hypermethylation has been detected in up to 70% of in ammatory human breast tumors 53 and 7% of metaplastic breast carcinomas 54 .…”

Diclofenac Induces Intrinsic Apoptotic Pathway in in Cervical Cancer Cells

“…[10] It has also been shown that inhibition of caspase-9 may block the autophagic flux and enhance cell death due to blockage of cytoprotective autophagy [11]. Previous experiments have demonstrated that non-steroidal anti-inflammatory drugs (NSAIDs) have chemopreventive effects on several cancers including those of cervix [12]. Diclofenac has shown anti-neoplastic effects by downregulating PI3-K/Akt/PTEN pathway and also inducing apoptosis [13].…”