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Caloric restriction inhibits mammary tumorigenesis in MMTV-ErbB2 transgenic mice through the suppression of ER and ErbB2 pathways and inhibition of epithelial cell stemness in premalignant mammary tissues.

ABSTRACT: Caloric intake influences the onset of many diseases, including cancer. In particular, caloric restriction (CR) has been reported to suppress mammary tumorigenesis in various models. However, the underlying cancer preventive mechanisms have not been fully explored. To this end, we aimed to characterize the anticancer mechanisms of CR using MMTV-ErbB2 transgenic mice, a well-established spontaneous ErbB2-overexpressing mammary tumor model, by focusing on cellular and molecular changes in premalignant tissues. In MMTV-ErbB2 mice with 30% CR beginning at 8 weeks of age, mammary tumor development was dramatically inhibited, as exhibited by reduced tumor incidence and increased tumor latency. Morphogenic mammary gland analyses in 15- and 20-week-old mice indicated that CR significantly decreased mammary epithelial cell (MEC) density and proliferative index. To understand the underlying mechanisms, we analyzed the effects of CR on mammary stem/progenitor cells. Results from fluorescence-activated cell sorting analyses showed that CR modified mammary tissue hierarchy dynamics, as evidenced by decreased luminal cells (CD24highCD49flow), putative mammary reconstituting unit subpopulation (CD24highCD49fhigh) and luminal progenitor cells (CD61highCD49fhigh). Mammosphere and colony-forming cell assays demonstrated that CR significantly inhibited mammary stem cell self-renewal and progenitor cell numbers. Molecular analyses indicated that CR concurrently inhibited estrogen receptor (ER) and ErbB2 signaling. These molecular changes were accompanied by decreased mRNA levels of ER-targeted genes and epidermal growth factor receptor/ErbB2 family members and ligands, suggesting ER-ErbB2 signaling cross-talk. Collectively, our data demonstrate that CR significantly impacts ER and ErbB2 signaling, which induces profound changes in MEC reprogramming, and mammary stem/progenitor cell inhibition is a critical mechanism of CR-mediated breast cancer prevention.

SUBMITTER: Ma Z

PROVIDER: S-EPMC6175030 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Caloric restriction inhibits mammary tumorigenesis in MMTV-ErbB2 transgenic mice through the suppression of ER and ErbB2 pathways and inhibition of epithelial cell stemness in premalignant mammary tissues.

Ma Zhikun Z Parris Amanda B AB Howard Erin W EW Shi Yujie Y Yang Shihe S Jiang Yunbo Y Kong Lingfei L Yang Xiaohe X

Carcinogenesis 20181001 10

Caloric intake influences the onset of many diseases, including cancer. In particular, caloric restriction (CR) has been reported to suppress mammary tumorigenesis in various models. However, the underlying cancer preventive mechanisms have not been fully explored. To this end, we aimed to characterize the anticancer mechanisms of CR using MMTV-ErbB2 transgenic mice, a well-established spontaneous ErbB2-overexpressing mammary tumor model, by focusing on cellular and molecular changes in premalig ...[more]

PMID: 30107476

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Project description:Overexpression of the NEDD9/HEF1/Cas-L scaffolding protein is frequent, and drives invasion and metastasis in breast, head and neck, colorectal, melanoma, lung and other types of cancer. We have examined the consequences of genetic ablation of Nedd9 in the MMTV-HER2/ERBB2/neu mouse mammary tumor model. Unexpectedly, we found that only a limited effect on metastasis in MMTV-neu;Nedd9(-/-) mice compared with MMTV-neu;Nedd9(+/+) mice, but instead a dramatic reduction in tumor incidence (18 versus 80%), and a significantly increased latency until tumor appearance. Orthotopic reinjection and tail-vein injection of cells arising from tumors, coupled with in vivo analysis, indicated tumors arising in MMTV-neu;Nedd9(-/-) mice had undergone mutational selection that overcame the initial requirement for Nedd9. To better understand the defects in early tumor growth, we compared mammary progenitor cell pools from MMTV-neu;Nedd9(-/-) versus MMTV-neu;Nedd9(+/+) mice. The MMTV-neu;Nedd9(-/-) genotype selectively reduced both the number and colony-forming potential of mammary luminal epithelial progenitor cells, while not affecting basal epithelial progenitors. MMTV-neu;Nedd9(-/-) mammospheres had striking defects in morphology and cell polarity. All of these defects were seen predominantly in the context of the HER2/neu oncogene, and were not associated with randomization of the plane of mitotic division, but rather with depressed expression the cell attachment protein FAK, accompanied by increased sensitivity to small molecule inhibitors of FAK and SRC. Surprisingly, in spite of these significant differences, only minimal changes were observed in the gene expression profile of Nedd9(-/-) mice, indicating critical Nedd9-dependent differences in cell growth properties were mediated via post-transcriptional regulation of cell signaling. Coupled with emerging data indicating a role for NEDD9 in progenitor cell populations during the morphogenesis of other tissues, these results indicate a functional requirement for NEDD9 in the growth of mammary cancer progenitor cells.

Dataset Information

Caloric restriction inhibits mammary tumorigenesis in MMTV-ErbB2 transgenic mice through the suppression of ER and ErbB2 pathways and inhibition of epithelial cell stemness in premalignant mammary tissues.

Publications

Caloric restriction inhibits mammary tumorigenesis in MMTV-ErbB2 transgenic mice through the suppression of ER and ErbB2 pathways and inhibition of epithelial cell stemness in premalignant mammary tissues.

Similar Datasets

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