The Multifaceted Role of STAT3 in Mammary Gland Involution and Breast Cancer

Hughes, Katherine; Watson, Christine J.

doi:10.3390/ijms19061695

Cited by 56 publications

(50 citation statements)

References 97 publications

(115 reference statements)

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“…Therefore, targeting pY705 site and pY+X site is an effective strategy for designing new STAT3 inhibitors 27 – 33 . Some of STAT3 inhibitors are on the clinical research, while there is still no STAT3 inhibitor antitumor drugs in the market 34 , 35 .…”

Section: Introductionmentioning

confidence: 99%

RETRACTED ARTICLE: A new synthetic derivative of cryptotanshinone KYZ3 as STAT3 inhibitor for triple-negative breast cancer therapy

Zhang

Cai

et al. 2018

Cell Death Dis

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Silencing STAT3 is confirmed as a promising therapeutic strategy for triple-negative breast cancer (TNBC) therapy to address the issue of its poor prognosis. In this study, the natural product cryptotanshinone was firstly remodeled and modified as a more effective STAT3 inhibitor by structure-based strategy. The synthetic derivative KYZ3 had 22–24-fold increase in antitumor activity than cryptotanshinone on two TNBC cell lines but had little effect on normal breast epithelial MCF-10A cells. Further investigation showed that KYZ3 inhibited persistent STAT3 phosphorylation. It also prevented the STAT3 protein nuclear translocation to regulate the expressions of the target oncogenes including Bax and Bcl-2. Furthermore, KYZ3 inhibited TNBC cell metastasis by decreasing the levels of MMP-9 which were directly regulated by activated STAT3. A STAT3 plasmid transfecting assay suggested that KYZ3 induced tumor cell apoptosis mainly by targeting STAT3. Finally, KYZ3 suppressed the growth of tumors resulting from subcutaneous implantation of MDA-MB-231 cells in vivo. Taken together, KYZ3 may be a promising cancer therapeutic agent for TNBC.

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Section: Introductionmentioning

confidence: 99%

RETRACTED ARTICLE: A new synthetic derivative of cryptotanshinone KYZ3 as STAT3 inhibitor for triple-negative breast cancer therapy

Zhang

Cai

et al. 2018

Cell Death Dis

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“…In line with these observations and in sharp contrast with the putative oncogenic role of STAT3 in breast cancer, it is intriguing to note that one of the first functions ascribed to STAT3 was the induction of cell death during mammary-gland involution. Thus, in the physiological setting of the post-lactation regression of the mammary tissue, the recruitment and activation of STAT3 orchestrates a complicated and finely regulated series of events, eventually leading to involution [ 10 , 28 ].…”

Section: Stat3 In Normal Mammary Gland and Developmentmentioning

confidence: 99%

“…In this work, however, we will only briefly describe details of STAT3 modulation and functions in normal and neoplastic cells or its crucial and pleiotropic roles in the tumor microenvironment, since these topics are very well and exhaustively reviewed by very recent works [ 1 , 10 ]. On the other hand, we will discuss in more detail the results from recent publications that highlighted a new and even more contradictory role of STAT3 during breast cancer progression, in local recurrences and distant metastases [ 11 , 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

STAT3 in Breast Cancer Onset and Progression: A Matter of Time and Context

Segatto

Baldassarre

Belletti

2018

IJMS

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Signal transducer and activator of transcription 3 (STAT3) is responsible for mediating the transcriptional programs downstream of several cytokine, growth factor, and oncogenic stimuli. Its expression and activity are consistently linked to cellular transformation, as well as tumor initiation and progression. Due to this central role, STAT3 is widely considered a good target for anti-cancer therapy; however, the success of these approaches has been, so far, very limited. Notably, on one side, STAT3 is aberrantly active in many breast cancers, on the other, at the physiological level, it is the main mediator of epithelial cell death during post-lactation mammary-gland involution, thus strongly suggesting that its biological functions are highly context-specific. One of the most peculiar features of STAT3 is that it can act both in cell-autonomous and non-cell-autonomous manners, simultaneously modulating the phenotypes of the tumor cells and their microenvironment. Here, we focus on the role of STAT3 in breast cancer progression, discussing the potential contrasting roles of STAT3 activation in the establishment of locally recurrent and distant metastatic disease. Based on the most recent literature, depending on the tumor cell type, the local microenvironment status, and the stage of the disease, either STAT3 activation or inactivation can support disease progression. Accordingly, cancer cells dynamically exploit STAT3 activity to carry out transcriptional programs somehow contrasting and complementary, such as supporting survival and growth, dormancy and awakening, stem cell-like features, and inflammation, immune response, and immune evasion. As a consequence, to achieve clinical efficacy, the conception and testing of anti-STAT3 targeted therapies will need a very careful evaluation of these opposing roles and of the most appropriate tumor context, disease stage and patient population to treat.

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“…Eosinophil recruitment to the prepubertal mouse mammary gland coincides with a dramatic increase in eotaxin mRNA transcript levels, and, like macrophages, eosinophils are thought to promote branching and formation of TEBs . Mast cells also exhibit fluctuations in number during different stages of mammary postnatal development , and numbers present during murine involution are influenced by mammary epithelial Stat3 signalling . Elaboration of plasma kallikrein, a plasminogen activator, may be one role of the connective tissue‐type mast cells associated with postlactational regression .…”

Section: Introductionmentioning

confidence: 99%

Dynamic architectural interplay between leucocytes and mammary epithelial cells

et al. 2019

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The adult mammary gland undergoes dynamic changes during puberty and the postnatal developmental cycle. The mammary epithelium is composed of a bilayer of outer basal, or myoepithelial, cells and inner luminal cells, the latter lineage giving rise to the milk-producing alveolar cells during pregnancy. These luminal alveolar cells undergo Stat3-mediated programmed cell death following the cessation of lactation. It is established that immune cells in the microenvironment of the gland have a role to play both in the ductal outgrowth during puberty and in the removal of dead cells and remodelling of the stroma during the process of postlactational regression. However, most studies have focussed on the role of the stromal immune cell compartment or have quantified immune cell populations in tissue extracts. Our recent development of protocols for deep imaging of the mammary gland in three dimensions (3D) has enabled the architectural relationship between immune cells and the epithelium to be examined in detail, and we have discovered a surprisingly dynamic relationship between the basal epithelium and leucocytes. Furthermore, we have observed morphological changes in the myoepithelial cells, as involution progresses, which were not revealed by previous work in 2D tissue sections and whole tissue. This dynamic architecture suggests a role for myoepithelial cells in the orderly progression of involution. We conclude that deep imaging of mammary gland and other tissues is essential for analysing complex interactions between cellular compartments.Abbreviations 2D, two dimensions; 3D, three dimensions; CD, cluster of differentiation; DAPI, 4 0 ,6-diamidino-2-phenylindole; DCIS, ductal carcinoma in situ; DCs, dendritic cells; DNA, deoxyribonucleic acid; GPI, glycosylphosphatidylinositol; H&E, haematoxylin and eosin; IgA, immunoglobulin A; K5, keratin 5; LIF, leukaemia inhibitory factor; MHCII, major histocompatibility complex class II; MIP, maximum intensity projection; MMPs, matrix metalloproteinases; NF-jB, nuclear factor kappa-light-chain-enhancer of activated B cells; SEMA, semaphorin; SMA, smooth muscle actin isoform a-actin; Stat, signal transducer and activator of transcription; TEBs, terminal end buds; Th, T helper; VEGF, vascular endothelial growth factor.

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The Multifaceted Role of STAT3 in Mammary Gland Involution and Breast Cancer

Cited by 56 publications

References 97 publications

RETRACTED ARTICLE: A new synthetic derivative of cryptotanshinone KYZ3 as STAT3 inhibitor for triple-negative breast cancer therapy

RETRACTED ARTICLE: A new synthetic derivative of cryptotanshinone KYZ3 as STAT3 inhibitor for triple-negative breast cancer therapy

STAT3 in Breast Cancer Onset and Progression: A Matter of Time and Context

Dynamic architectural interplay between leucocytes and mammary epithelial cells

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