DMBA induced mouse mammary tumors display high incidence of activating Pik3caH1047 and loss of function Pten mutations

Abstract

Controversy always existed on the utility of chemically induced mouse mammary carcinogenesis models as valid equivalents for the study of human breast cancer. Here, we performed whole exome and RNA sequencing on long latency mammary tumors (218 ± 27 days) induced by the carcinogen 7,12-Dimethylbenzathracene (DMBA) and short latency tumors (65 ± 11 days) induced by the progestin Medroxyprogesterone Acetate (MPA) plus DMBA in CD2F1 mice. Long latency tumors displayed a high frequency of Pi3kca and/or Pten mutations detected in 11 of 13 (85%) long latency cases (14/22, 64% overall). Eighty-two percent (9/11) of tumors carried the Pik3ca H1047L/R hot-spot mutation, as frequently found in human breast cancer. These tumors were luminal-like and mostly ER/PR+, as in humans. Transcriptome profiling indicated a significant activation of the PI3K-Akt pathway (p=3.82e-6). On the other hand MPA+DMBA induced short latency tumors displayed mutations in cancer drivers not commonly found mutated in human breast cancer (e.g. Hras and Apc). These tumors were mostly basal-like and MPA exposure led to Rankl overexpression (60 fold induction) and immunosuppressive gene expression signatures. In summary, long latency DMBA induced mouse mammary tumors reproduce the molecular profile of human luminal breast carcinomas representing an excellent preclinical model for the testing of PIK3CA/Akt/mTOR pathway inhibitory therapies and a good platform for the developing of additional preclinical tools such as syngeneic transplants in immunocompetent hosts.

7,12‐Dimethylbenz[α]anthracene increases cell proliferation and invasion through induction of Wnt/β‐catenin signaling and EMT process

“…These CYP1s metabolize DMBA into free radical intermediates, such as superoxide, hydrogen peroxide, and nitrogen oxide, which could generate a mutagenic DNA adduct through covalent binding to the exocyclic amino groups of purines or the induction of oxidative stress; subsequently, these events induce carcinogenesis . Recently, it was reported that the abrogation of the catalytic subunit of protein phosphatase ( Ppp6c ) accelerated DMBA‐induced tumorigenesis through NF‐κB activation and long‐term exposure to DMBA induced Pik3ca H1047 activation and Pten mutations with loss of function . Although these findings provided clues to the carcinogenic mechanism of DMBA, the detailed mechanism is still unknown.…”

“…[28][29][30][31][32] Recently, it was reported that the abrogation of the catalytic subunit of protein phosphatase (Ppp6c) accelerated DMBA-induced tumorigenesis through NF-jB activation and long-term exposure to DMBA induced Pik3ca H1047 activation and Pten mutations with loss of function. 33,34 Although these findings provided clues to the carcinogenic mechanism of DMBA, the detailed mechanism is still unknown.…”

Chemoprevention Effect of Curcuma Aeruginosa in Dmba-Induced Cytokines Production

“…Studies have observed main active compounds from terpenoid, such as curzerene, cineole, germacrone, and β-element to exhibit anti-cancer activities towards gastric cancer cell lines. Zhong et al also reported in his study that sesquiterpenoid germacrone exhibited the best anticancer properties by inhibiting cell proliferation, increasing lactate dehydrogenase, and mediating G1 and G2 cell cycle arrest in human breast cancer 10 . Other sesquisterpenes which consist of β, α, and γ-element has also been reported to exhibit anti-tumor activities and approved by the Food and Drug Administration of China as anti-cancer adjuvant drug on cancer patients 8 .…”

“…The rhizome of C. aeruginosa is traditionally used for the treatment of gastrointestinal problems, as well as an antimicrobial and anti-inflammatory agent. Other recent studies have also reported this rhizome to possess pharmacological activities for treating various diseases, such as tumor, asthma, and bronchitis [10][11] .…”

The Effect of E. scaber Extract to TNF-α and TGF-β on Mice under Carcinogen Treatment

“…The induction of DMBA and Estradiol carcinogen compounds for 8 weeks induced the formation of breast cancer 7,12-Dimethylbenz[a]anthracene (DMBA) was a carcinogen compound that has an aromatic hydrocarbon chain and has been widely used in research as an inducer in breast cancer modeling [22,23,24]. Estradiol is a steroid the sex hormone that useful in female reproductive cycle in regulation of estrous and menstrual cycles.…”