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

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

doi:10.1530/erc-20-0065

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 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.

Highlights

During 2011–2013, half the children born in the USA had an overweight or obese mother (Ogden et al 2015)
While we found no difference in the responses of primary tumors to TAM treatment between the control and high-fat diet (HFD) offspring, when therapy was completed and TAM was removed, the risk of local recurrence was over 90% in the HFD offspring, compared with less than 30% in the controls
The lack of difference in the response to cancer therapy is consistent with an earlier study in MMTV-Wnt1-Tg mice in which no differences in the response to doxycycline (Dox) chemotherapy in the control and HFD offspring were noted (Montales et al 2016)

Summary

Introduction

During 2011–2013, half the children born in the USA had an overweight or obese mother (Ogden et al 2015). Maternal obesity may increase a daughter’s breast cancer risk because high birth weight is strongly linked to both maternal obesity (Yu et al 2013) and an increased breast cancer risk among daughters (Michels et al 1996, Silva et al 2008). We earlier showed that maternal intake of an obesityinducing high-fat diet (HFD) increased pregnancy weight gain, caused high birth weight, and increased mammary cancer risk in female offspring (de Assis et al 2006). High birth weight has been linked to increased breast cancer mortality in humans (Sovio et al 2013)

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Results

Conclusion