Research Projects

Breast cancer is a major global health issue, comprising multiple molecular subtypes that differ in prognosis and treatment options. Among these, triple-negative breast cancer (TNBC) is highly aggressive, often affecting younger women and lacking effective targeted therapies. Therefore, uncovering the basic biology of TNBC is critical to finding targetable genes for treatment. Post-translational modifications (PTMs), particularly ubiquitination, are central to cancer progression. E3 ubiquitin ligases, such as cullins, require adaptor proteins to recognize substrates for degradation. We have identified an adaptor protein for Cullin ligases that is highly expressed only in TNBC and essential for TNBC cell survival, not for luminal breast cancer and normal epithelial cells. Depending on the context, these adaptors can act as oncogenes or tumor suppressors. Based on our strong preliminary data and literature, we hypothesize that KLHDC3 facilitates selective degradation of tumor-suppressors by interacting with cullins and mediates TNBC cell survival as a driver oncogene. To validate this, we aim to (1) evaluate KLHDC3 expression and function in TNBC cell lines and patient tumors, (2) identify KLHDC3-interacting proteins using pull-down assays and mass spectrometry in MDAMB-231/LM2 cells stably expressing KLHDC3 with a Turbo tag, and (3) map molecular interactions through mutational analyses with target protein and cullins. Lastly, (4) we will investigate upstream regulators of KLHDC3. In support of objective 4, our preliminary findings show that TGF-beta signaling induces KLHDC3 expression, indicating its role in epithelial-mesenchymal transition (EMT). The proposed study is highly novel as only 1-2 articles have been published on KLHDC3’s oncogenic role in lung cancer, and no study has been conducted on breast cancer. The study will provide an in-depth understanding of KLHDC3’s function in TNBC using in vitro models, patient samples, molecular and biochemical tools, and proteomic approaches. The outcomes may be a quality publication in a top-tier journal.