2018 • Health Sciences
Developing a Pre-Diagnostic for Chemotherapy in Triple Negative Breast Cancer
Lead Presenter: Shivahamy Maheswaran
PI: Valentine Comaills
Faculty Advisor: Nancy Hanrahan
As cancers grow, their centers receive less oxygen; a condition called hypoxia. Hypoxia induces cell death in the cancer cells located at the center. However, a minor fraction of cells survives. I hypothesized that these cells would be resistant to therapy. I tested my hypothesis using chemotherapy and Triple Negative Breast Cancers (TNBCs), a subtype of breast cancer predominantly treated with chemotherapy. The TNBC lines, BT549, MDA-MB-231, MDA-MB-468, and MDA-MB-157, were grown under hypoxia or normoxia, treated with increasing concentrations of docetaxel and doxorubicin, and cell viability was quantified. BT549 and MDA-MB-468 cells are more resistant to chemotherapy under hypoxia, compared with MDA-MB-157 and MDA-MB-231. To identify the mechanism underlying the differential drug sensitivity, l compared the entire transcriptomes of these cell lines. The TGFB pathway is downregulated in the resistant lines compared with the other lines. TGFß is known to induce epithelial to mesenchymal transition (EMT), a process linked to drug resistance. Thus, we tested whether EMT is responsible for the drug resistance observed under hypoxic conditions. BT549 and MDA-MB-468 cells, under hypoxia, lose their epithelial traits and become more mesenchymal, shown by decreased E-Cadherin and increased vimentin. Consistent with these findings, increased TGFß signaling in TNBC patients is associated with poor overall survival. Taken together, my work identifies two classes of TNBCs according to their drug responsiveness under hypoxia. Hypoxia-induced TGFB signaling in these TNBCs, through EMT, may confer drug resistance suggesting that TGFß inhibitors could overcome hypoxia-mediated resistance to chemotherapy in a subset of TNBCs.