Maternal Obesity Increases Tamoxifen Resistance In Female Rat Offspring

Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LAMore than 50% of pregnant women in the USA are overweight or obese, and over 40% gain more weight than recommended by the Institute of Medicine. We investigated if maternal obesity before and during pregnancy affects mammary cancer risk in the offspring, or alters response of the mammary tumors to antiestrogen therapy in a preclinical rat model of estrogen receptor positive (ER+) breast cancer.Female Sprague-Dawley rats were fed an obesity-inducing high fat (OIHF) or control diet before and during pregnancy. Their offspring were all switched to a control AIN93G diet upon birth. Female offspring of control (n = 35) or OIHF (n = 40) diet fed dams were treated with a carcinogen DMBA on postnatal day 50 to induce ER+ mammary tumors. When mammary tumors reached a size of 13 mm in diameter, 337 ppm TAM citrate was added to the offspringu0027s diet, resulting a daily intake of 15 mg/kg TAM. Responses of the tumors were categorized as de novo resistant (tumor kept growing), partial (size decreased but did not disappear), and complete (tumor disappeared). The animals with complete response were taken off from TAM and monitored for an additional 20 weeks to determine the risk of local recurrence.The risk of developing mammary tumors was non-significantly increased in the OIHF group. Further, the OIHF exposed offspring had significantly more de novo resistant tumors than the control offspring. Although the percentage of completely responding tumors was similar in the two groups, local recurrence in the OIHF offspring was significantly higher than in the control offspring (90% vs 29%, respectively). To investigate the possible mechanisms of increased recurrence, we measured the protein levels of the members of unfolded protein response (UPR), inflammation and tumor immune pathways. We found that de novo TAM resistant and recurring tumors in the OIHF offspring exhibited significantly increased levels of Perk and Beclin-1, indicating activation of UPR. However, Nbr1 and p62 were also significantly increased in the OIHF offspring, suggestive of inhibition of autophagy in their mammary tumors. The levels of CD8a, a marker of cytotoxic T cells, were significantly reduced, whilst ERα, erBb2/Her2 and Vegfr2 were increased. Changes in the expression of these receptors could indicate increased inflammation.We conclude that maternal obesity increased TAM resistance and the risk of mammary cancer recurrence in the female offspring. In addition, it induced changes in the UPR, autophagy and tumor immune responses in the offspringu0027s mammary tumors.Citation Format: Xiyuan Zhang, Idalia Cruz, Hansheng Zhang, Leena Hilakivi-Clarke. Maternal obesity increases tamoxifen resistance in female rat offspring. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4322.