Maternal obesity increases offspring s mammary cancer recurrence and impairs tumor immune response

Xiyuan Zhang, Fabia De Oliveira Andrade, Hansheng Zhang, Idalia Cruz, Robert Clarke, Pankaj Gaur, Vivek Verma, Leena Hilakivi-Clarke

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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 mate rnal 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 c an pre-program similar changes in the TME of allografted E0771 mammary tumors in offspr ing 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.

Original languageEnglish (US)
Pages (from-to)469-482
Number of pages14
JournalEndocrine-related cancer
Volume27
Issue number9
DOIs
StatePublished - 2020
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by U54-CA149147 and U01-CA184902 to R Clarke, and R01-CA164384 and A 阀CR grant to L Hilakivi-Clarke, and P30-CA51008 to Lombardi Comprehensive Cancer Center (funding for Shared Resources).

Keywords

  • Breast cancer
  • Inflammation
  • Local recurrence
  • Tamoxifen therapy
  • Tumor immune microenvironment

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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