Poly- and perfluoroalkylated substances (PFAS) are chemicals that persist and bioaccumulate in the environment and are found in nearly all human populations through several routes of exposure. Human occupational and community exposure to PFAS has been associated with several cancers, including cancers of the kidney, testis, prostate, and liver. While evidence suggests that PFAS are not directly mutagenic, many diverse mechanisms of carcinogenicity have been proposed. In this mini-review, we organize these mechanisms into three major proposed pathways of PFAS action—metabolism, endocrine disruption, and epigenetic perturbation—and discuss how these distinct but interdependent pathways may explain many of the proposed pro-carcinogenic effects of the PFAS class of environmental contaminants. Notably, each of the pathways is predicted to be highly sensitive to the dose and window of exposure which may, in part, explain the variable epidemiologic and experimental evidence linking PFAS and cancer. We highlight testicular and prostate cancer as models to validate this concept.
Testicular germ cell tumors (TGCTs) are aggressive but sensitive to cisplatin-based chemotherapy.Alternative therapies are needed for tumors refractory to cisplatin with hypomethylating agents providing one possibility. The mechanisms of cisplatin hypersensitivity and resistance in TGCTs remain poorly understood. Recently, it has been shown that TGCTs, even those resistant to cisplatin, are hypersensitive to very low doses of hypomethylating agents including 5-aza deoxy-cytosine (5aza) and guadecitabine. We undertook a pharmacogenomic approach in order to better understand mechanisms of TGCT hypomethylating agent hypersensitivity by generating a panel of acquired 5aza resistant TGCT cells and contrasting these to previously generated acquired isogenic cisplatin resistant cells from the same parent. Interestingly, there was a reciprocal relationship between cisplatin and 5-aza sensitivity, with cisplatin resistance associated with increased sensitivity to 5-aza and 5-aza resistance associated with increased sensitivity to cisplatin. Unbiased transcriptome analysis revealed 5-aza resistant cells strongly downregulated polycomb target gene expression, the exact opposite of the finding for cisplatin resistant cells which upregulated polycomb target genes.This was associated with a dramatic increase in H3K27me3 and decrease in DNMT3B levels in 5aza resistant cells, the exact opposite changes seen in cisplatin resistant cells. Evidence is presented that reciprocal regulation of polycomb and DNMT3B may be initiated by changes in DNMT3B levels as DNMT3B knockdown alone in parental cells resulted in increased expression of H3K27me3, EZH2 and BMI1, conferred 5-aza resistance and cisplatin sensitization, and mediated genome-wide repression of polycomb target gene expression. Finally, genome-wide analysis revealed that 5-aza resistant, cisplatin resistant and DNMT3B knockdown cells alter the expression of a common set of polycomb target genes. This study highlights that reciprocal epigenetic changes mediated by DNMT3B and polycomb may be a key driver of the unique cisplatin and 5-aza hypersensitivity of TGCTs and suggests that distinct epigenetic vulnerabilities may exist for pharmacological targeting of TGCTs.
Breast cancer has the second-highest cancer mortality rate for women in the United States. There are effective therapies available and a growing list of biomarkers for prognosis. However, new breast cancer targets are critically needed for patients refractory to available therapies. The present study evaluates the role of gap 0 switch 2 (G0S2), in breast cancer. Using online databases, we observed G0S2 expression is downregulated in patients with estrogen receptor-positive (ER+) breast cancer and patients with high G0S2 expression have a lower rate of relapse after treatment. Previously, our lab showed G0S2 overexpression in ER+ breast cancer cell lines resulted in decreased proliferation. Further knockout of G0S2 in murine embryonic fibroblast resulted in higher oncogenic transformation and resistance to mTOR inhibitors. These results suggest that G0S2 has a tumor suppressive function in ER+ breast cancer. To test whether G0S2 has a role in ER-negative breast cancer global knockout of G0S2 was engineered in the ER-negative MMTV-PyMT transgenic mouse model. Slower tumor progression and decreased lung metastasis was observed in G0S2-null transgenic females compared to wild-type transgenic females. These data suggest that the role of G0S2 in breast cancer in dependent on ER-status, where G0S2 functions as a tumor suppressor in ER-positive breast cancer and a tumor promoter in ER-negative breast cancer. Molecular and genetic studies manipulating G0S2 and ER in various breast cancer contexts are ongoing and will help elucidate that precise role of G0S2 in breast cancer and provide clarity on the potential of G0S2 as a novel prognostic marker and therapeutic target. Citation Format: Andrea K. Corbet, Emmanuel Bikorimana, Ratnakar Singh, Zeeshan Fazal, Raya I. Boyd, Sarah Freemantle, Michael J. Spinella. Elucidating the role of G0S2 in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2488.
Testicular germ cell tumors (TGCTs) are the most frequent solid cancers of males between the ages of 16 to 39 and have the highest mortality in this age group. Testicular cancer is highly curable with platinum-based chemotherapeutics. However, 15-20% of patients are resistant and succumb to their disease. The mechanisms for cisplatin sensitivity/resistance in testicular cancer is unclear. Previously we showed that cisplatin refractory testicular cancer is highly sensitive to the DNA methyltransferase inhibitors (DNMTi), 5-Aza-2'-deoxycytidine (5-AZA-DC) and guadecitabine in vivo and in vitro. High expression of DNMT3B correlates with sensitivity to DNMTi in TGCT cells. Based on these preclinical findings we recently completed a phase 1 clinical trial which demonstrated the combination of guadecitabine and cisplatin was tolerable and effective in treating patients with platinum refractory germ cell cancer. To better understand the mechanism of chemotherapy sensitivity/resistance in testicular cancer we generated a series of cisplatin resistant cell models. Genome wide methylome array and de novo transcriptional profiling of cisplatin resistant TGCT cells revealed decreased global H3K27 methylation due to suppression of the polycomb repressive complex 2 (PRC2 ). To better understand the relationship between cisplatin and 5-AZA-DC sensitivity, 5-AZA-DC resistant testicular cancer cells were also generated. Remarkably, there was a reciprocal relationship between cisplatin and 5-AZA-DC resistance, with cisplatin resistance associated with increased sensitivity to 5-AZA-DC and 5-AZA-DC resistance associated with increased sensitivity to cisplatin. Transcriptomics profiling and other studies in 5-AZA-DC resistant cells revealed increased H3K27me3, repression of polycomb target genes and a dramatic decreased in DNMT3B expression, the exact opposite of the situation in cisplatin resistant cells. Further knockdown of DNMT3B resulted in induction of H3K27me3, decreased sensitivity to 5-AZA-DC and increased sensitivity to cisplatin. These data suggest that DNA methylation and polycomb signaling are interconnected drivers of chemotherapy and epigenetic therapy responses in TGCTs. Ongoing H3K27 me3 ChIP-Seq, global methylation analysis, and validation studies will be described to further elucidate these mechanisms with the goal of devising novel epigenetic-based therapies for testicular and potentially other cancers. Citation Format: Ratnakar Singh, Emmanuel Bikorimana, Zeeshan Fazal, Cliff Yerby, Hannah Baldwin, Aleyah Destiny Hattab, Megan Tomlin, Andrea K. Corbet, Raya Iman Boyd, Khadeeja Shahid, Doha Naguib Ahmed Mohamed Shokry, Sarah Joy Spinella, Michael J. Spinella. Polycomb signaling reciprocally regulates sensitivity of testicular germ cell tumors cells to cisplatin and DNA hypomethylating agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2127.
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