Maternal obesity increases offspring's mammary cancer recurrence and impairs tumor immune response
| Autor: | Pankaj Gaur, Xiyuan Zhang, Hansheng Zhang, Fábia de Oliveira Andrade, Vivek Verma, Robert Clarke, Leena Hilakivi-Clarke, Idalia Cruz |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research medicine.medical_specialty Offspring Endocrinology Diabetes and Metabolism DMBA Breast Neoplasms GZMB Obesity Maternal Rats Sprague-Dawley 03 medical and health sciences 0302 clinical medicine Endocrinology Immune system breast cancer Pregnancy Internal medicine medicine Animals Humans Tumor microenvironment Mammary tumor tumor immune microenvironment business.industry Research Immunity food and beverages Antiestrogen tamoxifen therapy 030104 developmental biology Oncology inflammation 030220 oncology & carcinogenesis Female Neoplasm Recurrence Local local recurrence business Tamoxifen hormones hormone substitutes and hormone antagonists medicine.drug |
| Zdroj: | Endocrine-Related Cancer |
| ISSN: | 1479-6821 |
| Popis: | Over 50% of women at a childbearing age in the United States are overweight or obese, and this can adversely affect their offspring. We studied if maternal obesity-inducing high fat diet (HFD) not only increases offspring’s mammary cancer risk but also impairs response to antiestrogen tamoxifen. Female rat offspring of HFD and control diet-fed dams, in which estrogen receptor-positive (ER+) mammary tumors were induced with the carcinogen 7,12-dimethylbenz[a]anthracene (DMBA), exhibited similar initial responses to antiestrogen tamoxifen. However, after tamoxifen therapy was completed, almost all (91%) tumors recurred in HFD offspring, compared with only 29% in control offspring. The increase in local mammary tumor recurrence in HFD offspring was linked to an increase in the markers of immunosuppression (Il17f, Tgfβ1, VEGFR2) in the tumor microenvironment (TME). Protein and mRNA levels of the major histocompatibility complex II (MHC-II), but not MHC-I, were reduced in the recurring DMBA tumors of HFD offspring. Further, infiltration of CD8+ effector T cells and granzyme B+ (GZMB+) cells were lower in their recurring tumors. To determine if maternal HFD can pre-program similar changes in the TME of allografted E0771 mammary tumors in offspring of syngeneic mice, flow cytometry analysis was performed. E0771 mammary tumor growth was significantly accelerated in the HFD offspring, and a reduction in the numbers of GZMB and non-significant reduction of interferon γ (IFNγ) secreting CD8+ T cells in the TME was seen. Thus, consumption of a HFD during pregnancy increases susceptibility of the female rat and mouse offspring to tumor immune suppression and mammary tumor growth and recurrence. |
| Databáze: | OpenAIRE |
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