miércoles, 2 de noviembre de 2016

La acumulación de grupos de zinc intracelulares específicos de subtipos se asocia con el fenotipo maligno en el cáncer de mama

Resultado de imagen de cáncer de mama

Background

Breast cancer is a heterogeneous disease at the molecular, histopathological, and clinical level. Through gene expression profiling, four subtypes based on expression of estrogen receptor (ER), progesterone receptor (PR), and epidermal growth factor receptor 2 (HER2) are recognized including: Luminal A (ER+/PR+/HER2), Luminal B (ER+/PR+/HER2+), Basal (ER/PR/HER2) and HER2- enriched (ER/PR/HER2+). These subtypes differ in incidence [], aggressiveness, and response to therapy []. Recently, it has been reported that breast tumors accumulate zinc (Zn) to levels well above those observed in normal tissue []. The degree of Zn accumulation is associated with cancer progression [] and malignancy []. However, the mechanisms responsible for Zn accumulation, and the relationship between Zn accumulation and breast cancer subtype are not understood.
A multitude of cellular processes are regulated by Zn including transcription, cell signaling, proliferation, invasion, apoptosis, and autophagy []. Cellular Zn metabolism is tightly regulated by a “Zn transporting network” which consists of 24 Zn transporting proteins that transport Zn into discrete sub-cellular compartments. The ZnT family of Zn transporters (SLC30A1-10 gene family) contains 10 members (ZnT1-10) [] that export Zn from the cytoplasm, either directly across the cell membrane or into intracellular compartments. The ZIP family of Zn transporters (SLC39A1-14 gene family) contains 14 members (ZIP1-14) [] and facilitates Zn import into the cytoplasm, either from across the cell membrane or from within a sub-cellular compartment. Cellular Zn management is also regulated by metallothioneins (MTs) [], which are Zn binding proteins that buffer cytoplasmic Zn. ZnT2-mediated Zn accumulation into vesicles and MT-binding are the two primary mechanisms through which cells protect themselves from Zn toxicity, and both are positively regulated by Zn exposure through the activation of four metal responsive elements (MREs) in their promoters [].
Over-expression of several Zn transporters (ZIP6, ZIP7, ZIP10, and ZnT2) [] is associated with Zn hyper-accumulation in breast tumors and several breast cancer cell lines. ZIP6 over-expression has been noted in ER+ subtypes [] and is associated with less aggressive tumors []. Similarly, ZnT2 over-expression accumulates Zn in vesicles which protects ER+ T47D cells from Zn toxicity []. In contrast, ZIP10 is over-expressed in highly invasive, basal-like cell lines (MDA-MB-231 and MDA-MB-435S cells) and potentiates invasion []. Similarly, ZIP7 over-expression in tamoxifen-resistant MCF7 cells is associated with enhanced motility []. In addition to Zn transporters, MT over-expression is documented in ~88 % of invasive ductal carcinoma tissue biopsies [], and is generally associated with poor prognosis [] and high histological grade []. However, reports of Zn transporter dysregulation are sporadic and a comprehensive analysis of Zn management in specific breast cancer subtypes has not been reported.
We reasoned that the molecular portrait of the Zn transporting network may be very different between malignant subtypes, and perhaps even a driver of their phenotypic behaviors. Herein, we used targeted genomic, proteomic, and Zn profiling in breast tumors and malignant cell lines that have characteristic features of Luminal (low-invasive, ER+/PR+/HER2; T47D cells) and Basal (highly invasive, ER/PR/HER2; MDA-MB-231 cells) subtypes. We observed subtype-specific differences in Zn management between Luminal and Basal breast tumors, and in cell culture models of luminal and basal-like breast cancer cells. Importantly, we found that Zn sequestration in vesicles through expression of ZnT2 profoundly reduced the proliferative and invasive phenotype of MDA-MB-231 cells, indicating that Zn dysregulation is subtype-specific, which may inform the development of novel diagnostic or therapeutic strategies.

Results

The distribution of Zn accumulation in breast tumors differs between Luminal and Basal tumors

We first utilized X-ray fluorescence microscopy to determine the spatial distribution of Zn in Luminal and Basal tumors and adjacent normal tissue (Fig. 1). Spatial analysis revealed differences in Zn content and localization within the malignant regions. In Luminal breast tumors, Zn primarily accumulated around the tumor periphery. In Basal breast tumors, Zn was more evenly distributed throughout the malignant tissue. When compared with the distribution of calcium (Ca), some differences were noted such that Zn overlapped closely with Ca in Basal tumors, but this was less consistent in Luminal tumors.

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