Session 1

MAY 17 / 15:30 - 17:00

Tumor heterogeneity and breast cancer therapy

AMGEN-LOGO

CHAIRS

Isabel Frahm

SANATORIO
MATER DEI

Albana Gattelli

IFIBYNE-UBA
CONICET

Marina Simian

INS-UNSAM
CONICET

SPEAKERS

Cancer targeted therapy and tumor heterogeneity: Act locally, think globally

Mohamed Bentires-Alj

Each year over 2.1 million new cases of breast cancer occur among women worldwide and 600,000 women die from this disease. In most cases, metastasis is the cause of death. Indeed, while 98% of patients survive 5 years or more after being diagnosed with a localized (confined to the primary site) breast cancer, this number drops to 15-25% if the cancer has metastasized to distant organs. Curing metastatic breast cancer clearly represents an unmet medical need.
Although progress has been made in broadly understanding breast tumor biology and progression to metastases, most of the relevant molecules and pathways remain undefined. The thread connecting the research in my lab is tumor heterogeneity. We assess mechanisms that influence normal and neoplastic breast stem cells, metastasis, and resistance to targeted therapies at the molecular, cellular, and whole organism levels considering both cell autonomous and non-cell autonomous mechanisms. We have also developed a personalized breast cancer treatment program.

Triple-negative breast cancer subtyping: why bother?

Jorge Reis-Filho

Metastasis-suppressor NME1 controls the invasive switch of breast cancer by regulating MT1-MMP surface clearance

(selected from posters)

Catalina Lodillinsky

Membrane Type 1 Matrix Metalloprotease (MT1-MMP) contributes to the invasive progression of breast cancers by degrading extracellular matrix tissues. Nucleoside diphosphate kinase, NME1/NM23-H1, has been identified as a metastasis suppressor; however, its contribution to local invasion in breast cancer is not known. Here, we report that NME1 is up-regulated in ductal carcinoma in situ (DCIS) as compared to normal breast epithelial tissues. NME1 levels drop in microinvasive and invasive components of breast tumor cells relative to synchronous DCIS foci. We find a strong anti-correlation between NME1 and plasma membrane MT1-MMP levels in the invasive components of breast tumors, particularly in aggressive histological grade III and triple-negative breast cancers. Knockout of NME1 accelerates the invasive transition of breast tumors in the intraductal xenograft model. At the mechanistic level, we find that MT1-MMP, NME1 and dynamin-2, a GTPase known to require GTP production by NME1 for its membrane fission activity in the endocytic pathway, interact in clathrin-coated vesicles at the plasma membrane. Loss of NME1 function increases MT1-MMP surface levels by inhibiting endocytic clearance. As a consequence, the ECM degradation and invasive potentials of breast cancer cells are enhanced. This study identifies the down-modulation of NME1 as a potent driver of the in situ-to invasive transition during breast cancer progression.