Novel Kinase Inhibitor Screen on Estrogen Receptor (ER)-positive Breast Cancer and ER Mutants




Rinderle, Caroline
Bunnell, Bruce


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Purpose: Breast cancer is the second leading cause of death in women in the United States. Triple-negative breast cancer is named for its lack of estrogen (ER), progesterone (PR) receptors, and HER2. The lack of receptors makes these tumors increasingly more challenging to treat, resulting in worse clinical outcomes than other receptor-positive subtypes. Some ER-positive tumors mutate to express an ER-negative phenotype, effectively reducing sensitivity to common anti-estrogenic drugs and making them more triple-negative and metastatic. Most estrogen-receptor mutations (both naturally occurring and genetically engineered) in ER-positive breast cancers occur at the ligand-binding site, rendering them ineffective. This change in estrogen receptor effectiveness can alter signaling cascades and affect downstream events in the cell, thereby promoting uncontrolled cell growth and insensitivity to drugs. Kinases are responsible for signal propagation in cells. Therefore, alterations to estrogen receptor signaling could significantly affect kinase expression and activity. Little is known about the 538 kinases encoded in the human kinome; consequently, they must be studied more thoroughly. Suppose a kinase inhibitor drug effectively inhibits the growth of cells with mutated estrogen receptors. In that case, there may be an effective treatment option against triple-negative breast cancer and these naturally occurring mutations. Methods:Wild-type ER-positive breast cancer cells (MCF-7) were treated with 1µM KCGS Drug Library kinase inhibiting compounds from Dr. David Drewry at the SGC at UNC Chapel Hill. After 72 hours, cells were stained with crystal violet and imaged for cellular viability and morphologic changes. In addition, ER-mutated ER-positive breast cancer cells (MCF-7 Y537S and MCF-7 S167A) were treated with the same compounds at 100nM for 72 hours and stained with crystal violet. Results: The data from the screening indicate that eight kinase inhibitors affected the morphology and viability of Y537S and S167A mutants to a greater extent than the wild-type MCF-7 cells at a log-dose lower concentration. One kinase inhibitor affected the S167A mutant to a greater extent than the Y537S mutant at the same attention (100nM). Conclusions:Mutations to the estrogen receptor of typically ER-positive breast cancers may give insight into the development of interventions for triple-negative breast cancers. In the future, additional ER mutants will be screened against the same kinase inhibitors. In addition, kinase inhibitors may also give insight into the kinases essential to cancer viability and metastasis.