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?Np63 regulates the expression of hyaluronic acid-related genes in breast cancer cells.

ABSTRACT: Triple negative breast cancers (TNBC) represent the most aggressive and clinically relevant breast carcinomas. On the basis of specific molecular signature, the majority of TNBC can be classified as basal-like breast carcinoma. Here, we report data showing that in basal-like breast carcinoma cells ?Np63 is capable of sustaining the production of the hyaluronic acid (HA), one of the major component of the extracellular matrix (ECM). At molecular level, we found that ?Np63 regulates the expression of HA-related genes, such as the HA synthase HAS3, the hyaluronidase HYAL-1 and CD44, the major HA cell membrane receptor. By controlling this pathway, ?Np63 contributes to maintain the self-renewal of breast cancer stem cells. Importantly, high HAS3 expression is a negative prognostic factor of TNBC patients. Our data suggest that in basal-type breast carcinoma ?Np63 might favor a HA-rich microenviroment, which can sustain tumor proliferation and stemness.

SUBMITTER: Gatti V

PROVIDER: S-EPMC6107578 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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ΔNp63 regulates the expression of hyaluronic acid-related genes in breast cancer cells.

Gatti Veronica V Fierro Claudia C Compagnone Mirco M Giangrazi Federica F Markert Elke Katrin EK Bongiorno-Borbone Lucilla L Melino Gerry G Peschiaroli Angelo A

Oncogenesis 20180824 8

Triple negative breast cancers (TNBC) represent the most aggressive and clinically relevant breast carcinomas. On the basis of specific molecular signature, the majority of TNBC can be classified as basal-like breast carcinoma. Here, we report data showing that in basal-like breast carcinoma cells ΔNp63 is capable of sustaining the production of the hyaluronic acid (HA), one of the major component of the extracellular matrix (ECM). At molecular level, we found that ΔNp63 regulates the expression ...[more]

PMID: 30139970

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Project description:Fatty acid synthase (FASN), the key enzyme for endogenous synthesis of fatty acids, is overexpressed and hyperactivated in a biologically aggressive subset of sex steroid-related tumors, including breast carcinomas. Using pharmacological and genetic approaches, we assessed the molecular relationship between FASN signaling and estrogen receptor alpha (ER?) signaling in breast cancer. The small compound C75, a synthetic slow-binding inhibitor of FASN activity, induced a dramatic augmentation of estradiol (E2)-stimulated, ER?-driven transcription. FASN and ER? were both necessary for the synergistic activation of ER? transcriptional activity that occurred following co-exposure to C75 and E2: first, knockdown of FASN expression using RNAi (RNA interference) drastically lowered (>100 fold) the amount of E2 required for optimal activation of ER?-mediated transcriptional activity; second, FASN blockade synergistically increased E2-stimulated ER?-mediated transcriptional activity in ER?-negative breast cancer cells stably transfected with ER?, but not in ER?-negative parental cells. Non-genomic, E2-regulated cross-talk between the ER? and MAPK pathways participated in these phenomena. Thus, treatment with the pure antiestrogen ICI 182?780 or the potent and specific inhibitor of MEK/ERK, U0126, was sufficient to abolish the synergistic nature of the interaction between FASN blockade and E2-stimulated ER? transactivation. FASN inhibition suppressed E2-stimulated breast cancer cell proliferation and anchorage-independent colony formation while promoting the reduction of ER? protein. FASN blockade resulted in the increased expression and nuclear accumulation of the cyclin-dependent kinase inhibitors p21WAF1/CIP1 and p27Kip1, two critical mediators of the therapeutic effects of antiestrogen in breast cancer, while inactivating AKT, a key mediator of E2-promoted anchorage-independent growth. The ability of FASN to regulate E2/ER? signaling may represent a promising strategy for anticancer treatment involving a new generation of FASN inhibitors.

Dataset Information

?Np63 regulates the expression of hyaluronic acid-related genes in breast cancer cells.

Publications

ΔNp63 regulates the expression of hyaluronic acid-related genes in breast cancer cells.

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