ING4 tumor suppressor and chemotherapy resistance in triple negative breast cancer
Breast cancer is subtyped based on the presence of hormone receptors (estrogen and progesterone) and HER2 receptors on the cancer cells. Triple negative breast cancer (TNBC) is defined by the lack of all three receptors and accounts for 15-20% of breast cancers. TNBC is an aggressive form of the disease associated with high rates of recurrence and mortality within five years. ING4 is a tumor suppressor gene deleted in 16.5% and downregulated in 34% of breast tumors. The correlation of ING4 deficiencies with tumor aggressiveness and poor patient survival implicates its tumor suppressive role in breast cancer. However, the exact methods by which ING4 deficiencies contribute to aggressive tumor progression are currently not well understood. We investigated the role of ING4 in TNBC by utilizing the TNBC cell line MDAmb231 genetically engineered to overexpress or delete ING4. Cell growth, cell migration, and sensitivity to doxorubicin, a chemotherapeutic agent, were compared between the ING4-modified cell lines. The results show that cell growth was comparable between the ING4-modified cell lines, indicating that ING4 does not play a role in determining the growth rates of TNBC. Cell migration rates over 6 hours were comparable between the ING4-modified cell lines, demonstrating that ING4 does not affect cancer cell motility. Cell viability decreased by 20% with ING4 deletion at 10 nM of doxorubicin, while cell viability increased by 20% with ING4 overexpression at 10 nM of doxorubicin in comparison to vector controls. This result shows a compelling trend in which ING4 deletion is correlated with decreased sensitivity to doxorubicin, while ING4 overexpression is correlated with increased sensitivity, suggesting that ING4 may determine chemotherapy response in TNBC. These findings suggest that tumors with low levels of ING4 may be more resistant to chemotherapy and thus require high dosage chemotherapy to treat.