Lack of breastfeeding as a risk factor for breast cancer: a strategy to address prevention
Spring Undergraduate Research Festival Presentation
Background: Epidemiological studies link lack of breastfeeding as a risk factor for breast cancer (BC), particularly triple-negative breast cancer. During pregnancy, the breast undergoes lobular differentiation to produce milk. Following lactation, the breast involutes (characterized by cell death) to near pre-pregnant stage. Extended breastfeeding (>6 months) allows gradual involution (GI), lack/short period of breastfeeding (< 3 months) causes abrupt involution (AI) of the breast. We modeled GI vs. AI in mice, revealing AI induces ductal hyperplasia and squamous metaplasia in mammary glands long after involution is complete. AI also induced increased cell proliferation and estrogen signaling, and chronic inflammation. Here, we test tamoxifen, a selective estrogen receptor modulator, as a preventive treatment to mitigate effects of AI.
Methods: Wild type FVB mice (at 8 weeks) were mated once and normalized to 6 pups/dam at partum. GI cohort pups were weaned after day28 (d28) postpartum (PP). AI cohort pups were weaned d7 PP to induce AI. For tamoxifen treatment, 5mg sustained release (60day) pellets were implanted in AI dams d8, d15, or d35 PP. Mammary glands were harvested d28 and d120 PP. H&E stained FFPE sections and immunohistochemistry was used to evaluate histology and cell proliferation/ inflammatory markers respectively.
Results: Tamoxifen treatment for 60days (as opposed to placebo) initiated on d8, d15 or d35 PP, completely abrogated hyperplastic changes, and markedly reduced cell proliferation and collagen deposition in AI glands harvested on d120 PP.
Conclusion: Previously we showed that estrogen signaling is increased in AI vs. GI glands. Here we report that blocking estrogen signaling with anti-estrogen tamoxifen can completely mitigate the precancerous changes induced by AI. These findings suggest that tamoxifen has potential as short term prophylactic treatment following lack/short period of breastfeeding to reduce BC risk.