Abstract
BackgroundBreast cancer is the second most diagnosed cancer globally accounting for over 2 million new worldwide cases of the disease in 2017. Chemotherapy (including cyclophosphamide and anthracyclines) is the mainstay for triple-negative breast cancer (TNBC) treatment. Despite high rates of responses to neoadjuvant chemotherapy, TNBC patients experience high rates of distant recurrence and less than 30% of patients with metastatic disease treated with chemotherapy will survive 5 years. These poor cancer patient outcomes highlight the need for novel companion diagnostics and therapies to identify the patients who will derive benefit and improve the response to therapy. Herein, we have identified ‘cell division cycle associated protein 3’ (CDCA3) as a novel protein that may prove useful to enhance chemotherapy response in TNBC. MethodsBioinformatics, Western blot, immunohistochemistry, siRNA depletion of CDCA3, CRISPR-Cas9 knockout, dose response, cell viability. ResultsCDCA3 transcripts are elevated across increasing grades of breast cancer, TNBC versus non-TNBC and in basal-like (BLIA and BLIS) versus luminal-AR and mesenchymal TNBC subtypes (METABRIC datasets). Elevated CDCA3 levels were strongly prognostic for patient outcome in high grade breast cancer and TNBC. Tissue microarray (TMA) immunohistochemistry analysis of over 300 breast cancers indicated heterogeneous CDCA3 staining is strongly prognostic in Ki67+ and TNBC cases of disease. CDCA3 staining correlated with markers of poor prognosis (nuclear grade, mitotic score, nuclear pleomorphism) and was associated with a poor prognosis. In vitro, we identified that, consistent with clinical data, CDCA3 levels were elevated in TNBC versus non-TNBC cell lines. In 10 TNBC cell lines, endogenous CDCA3 expression correlated with sensitivity to both cisplatin and doxorubicin, with CDCA3high levels having higher IC50 values and thereby being associated with a poor prognosis. Consistently, depleting these cells of CDCA3 markedly enhanced sensitivity to both cisplatin and doxorubicin. ConclusionsOur data highlight CDCA3 as a novel prognostic factor in TNBC that modulates sensitivity to chemotherapy. These findings point to the therapeutic potential of targeting CDCA3 in TNBC. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.
Published Version
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