Tagged: Mice

Sunscreen Ingredient Promotes Breast Cancer in Diet-Dependent Manner

In this high-Altmetric scoring Oncotarget paper, researchers examined the in vivo activity of benzophenone-3—a common ingredient in sunscreen and an endocrine-disrupting chemical—in a dietary context in mice to determine its potential role in promoting breast cancer.

In this high-Altmetric scoring Oncotarget paper, researchers examined the in vivo activity of benzophenone-3—a common ingredient in sunscreen and an endocrine-disrupting chemical—in a dietary context in mice to determine its potential role in promoting breast cancer.

Figure 2: BP-3 increased the proportion of epithelial tumors in mice fed an adult-restricted HFD.
Figure 2: BP-3 increased the proportion of epithelial tumors in mice fed an adult-restricted HFD.

The Top-Performer series highlights research literature published in Oncotarget that has generated a high Altmetric score. Altmetric scores, located at the top-left of trending Oncotarget papers, provide an at-a-glance indication of the volume and type of online attention the research has received. Read Oncotarget’s Top 100 Altmetric papers.

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Benzophenone-3 (BP-3 or oxybenzone) has been identified as a known endocrine-disrupting chemical (EDC) and, alarmingly, it is a common ingredient in many modern brands of sunscreen. BP-3 is also present in household dust, fish lipids, and due to its widespread human use, the water environment. Previous studies have shown that environmental toxins and estrogenic chemicals have emerged as potential culprits in the promotion of breast cancer. BP-3 in particular has been known to have estrogenic and anti-estrogenic properties.

“Although BP-3 has a very short half-life, its presence is widespread in human urine [9], in as much as 98% of the general U.S. population [13].”

Researchers, from the Breast Cancer and the Environment Research Program at Michigan State University, authored the paper, titled: “Benzophenone-3 promotion of mammary tumorigenesis is diet-dependent.” This study currently presents with an Altmetric Attention score of 65.

“We [previously] demonstrated enhancement of mammary tumorigenesis by a diet high in saturated animal fat (HFD) [58]. Thus, examination of the activity of EDCs in a dietary context may provide additional insight into the potential role of EDCs in promoting breast cancer.”

The Study

“We have shown that both estrogen [15, 16] and HFD [17, 5] can modulate proliferative, inflammatory and angiogenic activity in the mammary gland.” 

The researchers previously demonstrated the effects of a high-fat diet (HFD) in breast cancer. In the current study, they examined BP-3 in mice under three dietary conditions: mice fed a life-long low-fat diet (LFD), mice fed a low-fat diet during puberty and then a high-fat diet in adulthood (LFD-HFD), and mice fed a high-fat diet during puberty and then a low-fat diet in adulthood (HFD-LFD). 

Using the Trp53null transplantation model of basal-like breast cancer, both pubertal and adult mice were first placed on a LFD or HFD. Half of the mice were injected with BP-3, ovariectomized, given time for recovery and the natural dissipation of endogenous hormones, and then they were treated with 17β-estradiol (E2; estrogen) for five days. 

“This study identifies the effects of BP-3 on mammary tumorigenesis with high-fat diet during puberty versus adulthood in Trp53null transplant BALB/c mice. Thus, it is logical to test their individual and combined effects on mammary tumorigenesis.”

The mice in both variations of the HFD and LFD were fed their initial diet from three to ten weeks of age, and then switched to the other diet. Half of the mice were injected with BP-3 and the other half were used as the control groups.

“As BP-3 has known estrogenic and anti-estrogenic properties [9], and our studies herein show BP-3 enhanced estrogen-stimulated mammary proliferation, we examined estrogen levels in plasma from sacrificed tumor-bearing mice.”

Results

“We found that BP-3 had complex effects that were dependent upon dietary regimen and tumor histopathology.”

Consistent with the researchers’ earlier studies, most of the tumors in mice were epithelial in composition and some were spindle cell carcinomas. The LFD-HFD combination resulted in an increased proportion of spindle cell tumors compared to the LFD, however, the proportion of epithelial versus spindle cell tumors was also increased by BP-3 treatment in mice fed the LFD-HFD. 

“BP-3 did not significantly alter apoptosis, except for spindle cell tumors arising in mice fed LFD (Figure 6). Apoptosis in spindle cell tumors from LFD + BP-3 mice was reduced by half compared to those from LFD mice (Figure 6B).”

“Kaplan-Meier analysis revealed that BP-3 reduced tumorigenesis of epithelial tumors in mice fed LFD (Figure 3A). On the other hand, consistent with the increased proportion of epithelial tumors, BP-3 was promotional for epithelial tumorigenesis in mice fed LFD-HFD (Figure 3C), while reducing spindle cell tumorigenesis (Figure 3D).” 

Researchers saw that BP-3 treatment increased the number of lesions only in mice fed the HFD-LFD. Proliferation in all dietary groups was increased by BP-3 treatment. An analysis of variance (ANOVA) test found that BP-3 treatment only produced a significant effect on proliferation in the mammary glands of 26-week old mice.

“We observed a modest, but statistically significant, reduction in estrogen levels by BP-3 treatment of mice fed HFD-LFD.”

Importantly, the researchers note that, in this study and others, they observed a “pubertal window of susceptibility,” reinforcing that puberty is a highly sensitive window of time for adverse exposures. Ultimately, the team also found that BP-3 enhances estrogen-stimulated mammary gland proliferation in pubertal mice fed a HFD.

“Benzophenone-3 was protective for epithelial tumorigenesis in mice fed lifelong low-fat diet, while promotional for epithelial tumorigenesis in mice fed adult high-fat diet.”

Conclusion

Collectively, the researchers’ findings suggest that exposure to BP-3 may have adverse consequences in mammary tumorigenesis.

“Benzophenone-3 increased tumor cell proliferation, decreased tumor cell apoptosis, and increased tumor vascularity dependent on specific dietary regimen and tumor histopathology.”

“This points to a need for further studies of benzophenone-3 in both animal models and humans as a potential breast cancer risk factor, as well as a more general need to evaluate endocrine disrupting chemicals in varying dietary contexts.”

“Regarding BP-3, it will be valuable to eventually explore pubertal versus adult exposure to BP-3 on a constant diet regimen.”

“Nonetheless, BP-3 treatment clearly shows differential effects between the three dietary regimens.”

Click here to read the full scientific study, published in Oncotarget.

Oncotarget is a unique platform designed to house scientific studies in a journal format that is available for anyone to read—without a paywall making access more difficult. This means information that has the potential to benefit our societies from the inside out can be shared with friends, neighbors, colleagues and other researchers, far and wide.

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Trending with Impact: Bacterial Therapy Experiments in Prostate Cancer

Researchers reveal their positive findings from a study of bacterial cancer therapy using a strain of Salmonella typhimurium in mouse-modeled prostate cancer.

PC-3 human prostate cancer cells stained with blue Coomassie, under a differential interference contrast microscope. - Image
PC-3 human prostate cancer cells stained with blue Coomassie, under a differential interference contrast microscope.

The Trending with Impact series highlights Oncotarget publications attracting higher visibility among readers around the world online, in the news, and on social media—beyond normal readership levels. Look for future science news and articles about the latest trending publications here, and at Oncotarget.com.

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Over the past few decades, numerous studies have emerged using the promising strategy of bacteria as vehicles to deliver drugs or genes in tumor‐targeted therapies. Researchers say that bacterial cancer therapy may be able to overcome some of the limitations that conventional cancer therapy is stunted by, including the development of drug resistance. 

Researchers in this study—from Yale University in Connecticut, the University of Missouri, the Harry S. Truman Memorial Veterans Hospital, and the Cancer Research Center in Missouri, and DeSales University in Pennsylvania, U.S.—used a Salmonella typhimurium strain (CRC2631) of bacteria (previously reported to have tumor-targeting capabilities) in prostate cancer-positive mouse-models and evaluated its toxicity, targeting ability, and genetic stability.

“Here, we report the toxicological and in vivo tumor-targeting profiles of CRC2631 in the syngeneic and autochthonous mouse model of aggressive prostate cancer, TRAMP (Transgenic Adenocarcinoma of Mouse Prostate).”

“The B6FVB TRAMP model recapitulates some of the key genetic aspects of human prostate cancer.”

The Study

“VNP20009 is considered as the safety benchmark in bacterial cancer therapy development because it has been safely administered in human cancer patients [7, 30].”

“To determine the safety profile of CRC2631, we performed CRC2631 and VNP20009 comparative toxicological studies in TRAMP animals.”

The team focused on measuring toxicity through treatment-related weight loss and lethality. Groups of 14-week-old B6FVB TRAMP-positive mice were scanned using magnetic resonance imaging. Four mice were dosed with CRC2631, and four were dosed with VNP20009; both treated four times per week. Mice were weighed and monitored daily for four weeks.

Since the CRC2631 bacteria are cleared out through the liver, the researchers also sought to establish the impact of CRC2631 on liver pathology in this bacterial cancer therapy. Two groups of 31-week-old B6FVB TRAMP-positive mice were observed, one treated with four doses of CRC2631 and the other with saline (the control group) at three-day intervals. They used histological staining in the liver to observe differences in necrosis, inflammation, and extramedullary hematopoiesis between CRC2631 and the control group. The team then tested for lethality and the maximum tolerated dose of CRC2631.

“Next, we sought to determine the in vivo tumor-targeting capability of CRC2631 in TRAMP animals.”

Using fluorescence imaging and a chloramphenicol resistance cassette, researchers were able to observe the biodistribution of CRC2631 to determine its tumor-targeting capability in TRAMP-positive mice. Since they knew that CRC2631 is filtered through the liver and that enriched colonies may be found here, researchers used the liver as a way to compare the bacterial load in tumor tissues.

The researchers also tested CRC2631’s genetic stability by gauging its likelihood of regaining toxicity and/or losing tumor targeting capability by performing longitudinal, whole genome sequencing and short nucleotide polymorphism analyses.

“To determine the genetic stability of CRC2631 inside the host, we performed longitudinal whole genome sequencing and short nucleotide polymorphism (SNP) analyses of CRC2631 prior to treatment and tumor-passaged CRC2631 in B6 TRAMP (+) mice.”

In vitro, CRC2631 directly kills prostate cancer cells, however, in vivo, it does not lead to decreased tumor burden. The researchers believe this may be due to the effects of some kind of resistance mechanism in vivo, and tested a combined treatment method of CRC2631 and Invivomab—a checkpoint blockade—in the mouse model.

“CRC2631 targets and directly kills murine and human prostate cancer cells in vitro (Supplementary Figure 2), raising the possibility that unknown resistance mechanisms protect tumor cells from CRC2631-mediated cell death in vivo.”

Results

Researchers explain that in the first two weeks of the study, mice treated with CRC2631 and VNP20009 lost a comparable amount of weight. However, in the second half of the study, VNP20009-treated animals lost progressively more weight than those treated with CRC2631. This revealed that CRC2631 is less toxic than VNP20009.

“Consistent with CRC2631 being less toxic than VNP20009, the median survival time was 142 days for VNP20009 compared to 186 days for CRC2631 (Figure 1F).”

After evaluating effects in the liver from CRC2631, they found no differences between CRC2631 and the control group in liver necrosis, inflammation, or extramedullary hematopoiesis.

“Thus, in contrast to VNP20009, CRC2631 does not cause overt liver pathology.”

They established the maximum tolerated dose to be two doses of 5 × 10^7 colony forming units, administered three days apart. In the model used in fluorescence imaging, they found that CRC2631 was significantly colonized in the tumor tissue of mice when compared to colonization in the liver and, as the dosage increased, CRC2631 quantities in tumor tissues also increased.

“Taken together, these data indicate that CRC2631^iRFP720-cat targets primary tumors and metastases.”

Researchers revealed that it would take approximately 9375 days for CRC2631 to acquire a potential mutation in any specific gene. They determined CRC2631 to be a genetically stable tumor-targeting mechanism. Next, they collected results from the CRC2631 and Invivomab immune checkpoint blockade combination.

“We turned our focus to an interaction between CRC2631 and immune cells and asked whether tumor-targeted CRC2631 generates an anti-tumor immune response that tumors rapidly inhibit via immune checkpoint mechanisms.”

They found that tumor burdens were significantly reduced in the combination treatment method, and ultimately, that CRC2631 treatment with a checkpoint blockade combination reduces the metastatic burden in mouse-modeled prostate cancer.

Conclusion

The study as a whole revealed to the researchers that CRC2631 safely targets primary tumors and metastases, is less toxic than VNP20009, does not cause overt liver pathology, and that, in combination with an immune checkpoint blockade such as Invivomab, it reduces metastatic burden in vivo in B6FVB TRAMP-positive mice.

“These findings indicate that CRC2631 is a genetically stable biologic that safely targets tumors. Moreover, tumor-targeted CRC2631 induces anti-tumor immune activity and concordantly reduces metastasis burden in the setting of checkpoint blockade.”

With more research, this method may soon be studied as an effective clinical treatment option for human prostate cancer.

Click here to read the full scientific study, published in Oncotarget.

Oncotarget is a unique platform designed to house scientific studies in a journal format that is available for anyone to read—without a paywall making access more difficult. This means information that has the potential to benefit our societies from the inside out can be shared with friends, neighbors, colleagues and other researchers, far and wide.

For media inquiries, please contact media@impactjournals.com.