Mouse mammary tumor metastasis in response to oral contraceptives; adhesion, motility, and survival visualized by time lapse recording of normal, immortalized, and transformed metastatic human breast cell lines
Chiodo, Annalise Mary
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Breast cancer is the most commonly diagnosed cancer among US women. In general, breast cancer has relatively high overall survival rates, but still as many as 40,000 US women currently die of this disease each year. Up to 90% of these deaths occur after metastatic relapse, thus making metastasis one of the most important predictors of outcome. It is therefore of great importance to study interventions that can impact metastasis. Long term use of oral contraceptives (OC) have been shown to increase a woman’s overall chance of breast cancer by ∼24%, but has little effect on morbidity, suggesting that OC may inhibit metastasis. In order to test this hypothesis, we compared the effects of cyclic versus extended dosing regimens of OC on metastasis within a mouse model that gives rise to HER2 positive mammary gland tumors, a tumor type which often leads to metastases. We found that the administration of OCs in either dosing pattern did not have any significant effects on metastasis in the mouse model, in terms of incidence, multiplicity, or metastastic tumor pathophysiology. In order to compare in vitro normal and metastatic breast cancer cell culture models, we created a bank of time lapse videos of a “normal” immortalized breast epithelial cell line (MCF10A), an estrogen receptor positive epithelioid breast cancer cell line (MCF7), and a transformed, mesenchymal-like metastatic breast cancer cell line (MDA-MB-231). Cell line responses were compared for wound healing, growth at low density, and under conditions of low serum or exposure to an inducer of autophagy. As expected, MDA-MB-231 cells showed individualized amoeboid cell motility compared to the collective cell migration seen in epithelioid MCF10A and MCF7 cell lines. Contrary to our expectations, the MDA-MB- 231 cells grew slower and to a lower density than the more normal appearing breast cell lines, and were more susceptible to growth inhibition by low serum conditions. Treatment with a bacterial cytotoxin called LT-2C resulted in formation of autophagosomes only in the MDA-MB-231 cells; this was exacerbated by low serum conditions. We generated a library of high quality time lapse videos, posted as a YouTube Channel, available online for educational and research purposes. Visualizing the behavior of cell lines used to study breast cancer and metastasis, and discovering the metastatic impact of a popular prescription medication, are both important steps in studying how to prevent metastasis and decrease breast cancer mortality.