Timing of dietary exposures and tamoxifen resistance in rats
Hilakivi-Clarke, Leena A
In the USA, one in eight women develop invasive breast cancer at some point of her life, and 70% of the cancers are estrogen receptor positive and thus are treated with antiestrogen therapy. However, half of the treated patients exhibit resistance to tamoxifen, including de novo resistance and recurrence. By using a novel preclinical rat model, I studied the effect of timing of dietary components (genistein and obesity- inducing high fat) on mammary tumor responsiveness to tamoxifen therapy and the risk of recurrence.First, I studied timing of soy isoflavone genistein consumption and its effect on tamoxifen responsiveness in animals with ER+ mammary tumors. The results showed improved response to tamoxifen in animals that received genistein through their lifetime; they exhibited less de novo resistant and more complete responding tumors, compared with controls. Prepubertal and lifetime genistein intake also reduced the risk of recurrence, while the recurrence rate increased in rats that started genistein consumption during tamoxifen therapy.Next, I studied breast cancer responsiveness to tamoxifen and the rate of recurrence in the female offspring of obese and control dams. An obesity-inducing high fat diet was used to feed the dam Sprague-Dawley rats before and during pregnancy. Although maternal obesity induced by a high fat diet did not alter the tamoxifen responsiveness, it significantly increased the rate of mammary cancer recurrence in the offspring (91% vs 29%, obese offspring vs control, respectively).Furthermore, I evaluated expression of unfolded protein response (UPR), autophagy, apoptosis pathways and markers of tumors immune responses in the mammary glands and tumors before and after tamoxifen treatment. The results of molecular experiments showed changes of UPR and autophagy pathways that are associated with the tamoxifen response. More importantly, for both studies, the worse tamoxifen response and higher incidence of recurrence were associated with a reduction of cytotoxic T-cell marker CD8A and higher levels of regulatory T-cell markers Foxp3 and Tgfβ1 in the mammary tumors.In summary, I used a recently characterized ER+ breast cancer rat model and found that the timing of dietary exposures affected the tamoxifen response. I also demonstrated that the alterations in tamoxifen responsiveness and recurrence by diet were mediated through changes in UPR, autophagy, and tumor immune markers.
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