Letizia Lanzetti, Dr.
The recognized molecular heterogeneity of breast cancer translates into different disease course, therapeutic outcome and poses important questions in patients’ management. Strategies to achieve patients’ stratification for prognostic judgment and therapy assignments rely on the combined evaluation of clinical and pathological parameters, which more recently have been integrated by molecular signatures of aggressive disease. Together these tools have led to a largely accepted molecular classification (Luminal A and B, HER2+ and Basal-like/Triple-negative) that presently informs patients’ management (1). Among these molecular subtypes, Triple-negative breast cancers (TNBC) are defined by the absence of estrogen (ER) and progesterone (PR) receptors, and of ERRB2 expression. They represent 12%–17% of all breast tumors, more frequently affecting younger patients (2). Although presurgical chemotherapy results in high rates of clinical response, a large fraction of patients suffer from distant recurrence after surgery and poorer prognosis compared to other breast cancer patients (3-5). A major limitation in designing effective treatments for this group of breast cancers resides on their extreme heterogeneity. Identification of well-defined molecular targets to stratify patients and predict response is a currently unmet need in the TNBC population.
In the attempt to provide targets eligible to therapeutic treatment, extensive gene expression profiling has been performed in Triple-negative breast cancers. This has lead to the identification of distinct subtypes including one that displays unique gene ontologies of growth factors and receptor tyrosine kinase (RTK) signaling and glucose metabolism (5). Our laboratory focuses on molecules that control endocytosis of plasma membrane RTKs and nutrient transporters. Based on their role in RTKs signal propagation and nutrient uptake, they represent good candidates to be tested as markers of increased/derailed metabolic activity that can be targeted in TNBCs. Recently, we found that the RabGAP molecule USP6NL is amplified and overexpressed in around 10% of BCs, mainly of the Triple-negative subtype, predicting worse prognosis. Depletion of USP6NL, by regulating RTK signaling, causes degradation of the glucose transporter GLUT1, impairing glycolysis and cell proliferation, exclusively in TNBC cells that harbor increased amount of this molecule. In agreement, elevated USP6NL sensitizes BC cells to glucose deprivation indicating that their glycolytic capacity relies on this protein.
We plan to validate USP6NL as a predictive marker in TNBC and to extend our search for candidates that might dictate metabolic vulnerability in breast cancer.
1. Curigliano G, Burstein HJ, P Winer E, Gnant M, Dubsky P, Loibl S, et al. De-escalating and escalating treatments for early-stage breast cancer: the St. Gallen International Expert Consensus Conference on the Primary Therapy of Early Breast Cancer 2017. Ann Oncol 2017;28:1700-12
2. Foulkes WD, Smith IE, Reis-Filho JS. Triple-negative breast cancer. N Engl J Med 2010;363:1938-48
3. Haffty BG, Yang Q, Reiss M, Kearney T, Higgins SA, Weidhaas J, et al. Locoregional relapse and distant metastasis in conservatively managed triple negative early-stage breast cancer. J Clin Oncol 2006;24:5652-7
4. Dent R, Trudeau M, Pritchard KI, Hanna WM, Kahn HK, Sawka CA, et al. Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res 2007;13:4429-34
5. Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest 2011;121:2750-67