Cyclin D1 in Breast Cancer Pathogenesis

Taking a perspective on available evidence that emphasizes relevance to human disease, cyclin D1 is solidly established as an oncogene with an important pathogenetic role in breast cancer and other human tumors. However, the precise cellular mechanisms through which aberrant cyclin D1 expression drives human neoplasia are less well established. Indeed, emerging evidence suggests that cyclin D1 might act, predominantly or at least in part, through pathways that do not involve its widely accepted function as a cell cycle regulator. Although therapeutic exploitation of the role of cyclin D1 as a molecular driver of breast cancer carries great promise, it is also suggested that direct targeting of the cyclin D1 gene or gene products may prove more successful than approaches that rely on arguably incomplete knowledge of the oncogenic mechanisms of cyclin D1.

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Role of Cyclin D1 and cdk Inhibitors in Breast Cancer Pathogenesis

10.21236/ada407447 ◽

2002 ◽

Author(s):

Kristin Roovers ◽

R. K. Assoian

Keyword(s):

Breast Cancer ◽

Cyclin D1 ◽

Cdk Inhibitors ◽

Cancer Pathogenesis

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Intra-tumoral distribution of Ki-67 and Cyclin D1 in ER+ mammary carcinoma: quantitative evaluation

African Health Sciences ◽

10.4314/ahs.v21i1.7 ◽

2021 ◽

Vol 21 (1) ◽

pp. 41-6

Author(s):

Mohammedi Latifa ◽

Djillali Doula Fatima ◽

Mesli Farida ◽

Senhadji Rachid

Keyword(s):

Breast Cancer ◽

Cyclin D1 ◽

Poor Response ◽

Labeling Index ◽

Intratumor Heterogeneity ◽

Cellular Mechanisms ◽

Ki 67 ◽

Heterogeneous Distribution ◽

Er Positive

Background: In spite of the strong evidence demonstrating the role of overexpression of Ki-67 and Cyclin D1 markers in breast carcinomas, clinical and pathological data remain to be discussed. This can be explained partly by intratumor het- erogeneity. Objectives: To define the prevalence and clinical significance of Ki-67 and Cyclin D1 overexpression in primary breast tumors ER positive, while highlighting the existence of intratumor heterogeneity in this type of cancer. Materials and methods: 51 ER positive breast cancer tumors were used to evaluate the intratumoral distribution of Ki-67 and Cyclin D1 expression. Image acquisition and visualization of the markers were performed by optical microscopy and stereology sampling method. Results: The mean Ki-67 labeling index was distributed heterogeneously in the same tumor, from 20.67±6.87 to 45.10±10.65. The coefficient of variation (COV) revealed dispersion values between 13.4% and 42.9%. Associated with positive ER status, all the tumors presented a Cyclin D1 expression with a COV varying between 19% and 28.5% and a mean labeling index fluctuating between 19.40±4.42 and 41.64±10.08 within the same patient showing important intratumor heterogeneous distribution. Conclusion: In this study, we have adopted a strictly quantitative approach to evaluate and demonstrate intratumor hetero- geneity. This establishes one of the main factors for poor response to cancer therapy. To achieve this, intratumor heteroge- neity should be usually definable and quantifiable but this domain awaits future progress and methods need to move towards a better understanding of molecular and cellular mechanisms that initiate and maintain this tumor heterogeneity. Keywords: Breast cancer; Cyclin D1; ER+; Intra-tumoral heterogeneity; Ki-67.

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Antiproliferative Effect of Androgen Receptor Inhibition in Mesenchymal Stem-Like Triple-Negative Breast Cancer

Cellular Physiology and Biochemistry ◽

10.1159/000443052 ◽

2016 ◽

Vol 38 (3) ◽

pp. 1003-1014 ◽

Cited By ~ 24

Author(s):

Aiyu Zhu ◽

Yan Li ◽

Wei Song ◽

Yumei Xu ◽

Fang Yang ◽

...

Keyword(s):

Breast Cancer ◽

Androgen Receptor ◽

Cyclin D1 ◽

Cancer Cells ◽

Triple Negative Breast Cancer ◽

Breast Cancer Cells ◽

Triple Negative

Background/Aims: Androgen receptor (AR), a steroid hormone receptor, has recently emerged as prognostic and treatment-predictive marker in breast cancer. Previous studies have shown that AR is widely expressed in up to one-third of triple-negative breast cancer (TNBC). However, the role of AR in TNBC is still not fully understood, especially in mesenchymal stem-like (MSL) TNBC cells. Methods: MSL TNBC MDA-MB-231 and Hs578T breast cancer cells were exposed to various concentration of agonist 5-α-dihydrotestosterone (DHT) or nonsteroidal antagonist bicalutamide or untreated. The effects of AR on cell viability and apoptosis were determined by MTT assay, cell counting, flow cytometry analysis and protein expression of p53, p73, p21 and Cyclin D1 were analyzed by western blotting. The bindings of AR to p73 and p21 promoter were detected by ChIP assay. MDA-MB-231 cells were transplanted into nude mice and the tumor growth curves were determined and expression of AR, p73 and p21 were detected by Immunohistochemistry (IHC) staining after treatment of DHT or bicalutamide. Results: We demonstrate that AR agonist DHT induces MSL TNBC breast cancer cells proliferation and inhibits apoptosis in vitro. Similarly, activated AR significantly increases viability of MDA-MB-231 xenografts in vivo. On the contrary, AR antagonist, bicalutamide, causes apoptosis and exerts inhibitory effects on the growth of breast cancer. Moreover, DHT-dependent activation of AR involves regulation in the cell cycle related genes, including p73, p21 and Cyclin D1. Further investigations indicate the modulation of AR on p73 and p21 mediated by direct binding of AR to their promoters, and DHT could make these binding more effectively. Conclusions: Our study demonstrates the tumorigenesis role of AR and the inhibitory effect of bicalutamide in AR-positive MSL TNBC both in vitro and in vivo, suggesting that AR inhibition could be a potential therapeutic approach for AR-positive TNBC patients.

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Is it time to consider the Androgen receptor as a therapeutic target in breast cancer?

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520621666211201150818 ◽

2021 ◽

Vol 21 ◽

Author(s):

Melika Kooshki Forooshani ◽

Rosa Scarpitta ◽

Giuseppe Nicolò Fanelli ◽

Mario Miccoli ◽

Antonio Giuseppe Naccarato ◽

...

Keyword(s):

Breast Cancer ◽

Overall Survival ◽

Estrogen Receptor ◽

Androgen Receptor ◽

Prognostic Impact ◽

Nuclear Receptor Superfamily ◽

Cancer Pathogenesis ◽

Novel Biomarkers ◽

Tumorigenic Mechanism

: Breast cancer (BC) is a heterogeneous disease and the most prevalent malignant tumor in women worldwide. The majority of BC cases are positive for estrogen receptor (ER) and progesterone receptor (PgR), both known to be involved in cancer pathogenesis, progression, and invasion. In line with this, hormonal deprivation therapy appears to be a useful tool and an effective treatment for these BC subtypes. Unfortunately, prognosis among patients with hormone-negative tumors or therapy-refractory and metastatic patients remains poor. Novel biomarkers are urgently needed in order to predict the course of the disease, make better therapy decisions and improve the overall survival of patients. In this respect, the androgen receptor (AR), a member of the hormonal nuclear receptor superfamily and ER and PgR, emerges as an interesting feature widely expressed in human BCs. Despite the advances, the precise tumorigenic mechanism of AR and the role of its endogenous ligands are yet not well-understood. In this review, we aim to elaborate on the prognostic impact of AR expression and current AR-targeting approaches based on previous studies investigating AR's role in different BC subtypes.

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The Role of Fibroblast Growth Factors in Breast Cancer Pathogenesis and Progression

Breast Cancer ◽

10.1007/978-1-59259-456-6_3 ◽

1999 ◽

pp. 59-93

Author(s):

Francis G. Kern

Keyword(s):

Breast Cancer ◽

Growth Factors ◽

Fibroblast Growth Factors ◽

Fibroblast Growth ◽

Cancer Pathogenesis

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Progesterone Receptor B signaling Reduces Breast Cancer Cell Aggressiveness: Role of Cyclin-D1/Cdk4 Mediating Paxillin Phosphorylation

Cancers ◽

10.3390/cancers11081201 ◽

2019 ◽

Vol 11 (8) ◽

pp. 1201 ◽

Cited By ~ 2

Author(s):

Francesca Ida Montalto ◽

Francesca Giordano ◽

Chiara Chiodo ◽

Stefania Marsico ◽

Loredana Mauro ◽

...

Keyword(s):

Breast Cancer ◽

Cell Migration ◽

Progesterone Receptor ◽

Cyclin D1 ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Breast Epithelial Cell ◽

Luminal A ◽

Progesterone Receptor B

Progesterone-Receptor (PR) positivity is related with an enhanced response to breast cancer therapy, conversely cyclin D1 (CD1) is a retained marker of poor outcome. Herein, we demonstrate that hydroxyprogesterone (OHPg) through progesterone receptor B (PR-B) reduces breast cancer cell aggressiveness, by targeting the cytoplasmic CD1. Specifically, OHPg diminishes CD1 expression by a transcriptional regulation due to the recruitment of PR-B at a canonical half-PRE site of the CD1 promoter, together with HDAC1, determining a chromatin conformation less prone for gene transcription. CD1, together with its kinase partner Cdk4, regulates cell migration and metastasis, through the association with key components of focal adhesion, such as Paxillin (Pxn). Kaplan-Meier analysis shows that low Pxn expression was associated with increased distant metastasis-free survival in luminal A PR+ breast carcinomas. Interestingly, OHPg treatment reduced Pxn content in T47-D and MCF-7 cells; besides, the interaction between endogenous cytoplasmic CD1/Cdk4 with Pxn was reduced. This was consistent with the reduction of p-Ser83Pxn levels, crucially causing the delay in cell migration and a concomitant inhibition of Rac1 activity and p-PAK. Collectively, these findings support the role of PR-B in breast epithelial cell integrity and reinforce the importance in targeting PR-B as a potential strategy to restrict breast tumor cell invasion and metastasis.

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424 The Role of Cyclin D1 in Planning of Endocrine Therapy for Women of Postmenopausal Age with Breast Cancer

European Journal of Cancer ◽

10.1016/s0959-8049(12)70490-2 ◽

2012 ◽

Vol 48 ◽

pp. S170

Author(s):

V. Skvortsov ◽

G. Manikhas ◽

A. Manikhas ◽

A. Oganesyan ◽

G. Raskin

Keyword(s):

Breast Cancer ◽

Cyclin D1 ◽

Endocrine Therapy

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The Role of the Cyclin D1-Dependent Kinases in ErbB2-Mediated Breast Cancer

American Journal Of Pathology ◽

10.1016/s0002-9440(10)63190-2 ◽

2004 ◽

Vol 164 (3) ◽

pp. 1031-1038 ◽

Cited By ~ 24

Author(s):

Chuanwei Yang ◽

Viviana Ionescu-Tiba ◽

Karen Burns ◽

Michelle Gadd ◽

Lawrence Zukerberg ◽

...

Keyword(s):

Breast Cancer ◽

Cyclin D1

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The novel cytotoxicity of neutrophils in the peripheral blood of breast cancer patients versus women without breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.27_suppl.44 ◽

2011 ◽

Vol 29 (27_suppl) ◽

pp. 44-44

Author(s):

Z. Granot ◽

E. A. Comen ◽

L. Norton ◽

R. Benezra

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Peripheral Blood ◽

Primary Breast Tumor ◽

Newly Diagnosed ◽

Breast Cancer Patients ◽

Blood Samples ◽

Cell Kill ◽

A Cell

44 Background: Using murine mammary tumor models, recent research conducted by our laboratory at the Sloan-Kettering Institute indicates that select neutrophils are mobilized and entrained by a primary breast tumor and uniquely have the capacity to inhibit metastatic seeding in the lung (Granot Z et al. unpublished). We sought to determine whether entrainment of cytotoxic neutrophils also occurs in blood samples from women with newly diagnosed breast cancer as contrasted to those garnered from healthy women. Methods: Subjects were 21 newly diagnosed pre-operative breast cancer patients without evidence of metastatic disease, 9 healthy female volunteers with no history of any cancer, and 3 patients with newly diagnosed DCIS. Neutrophils were purified from the blood samples. Cytotoxicity was evaluated by incubating isolated neutrophils with luciferase labeled MDA-MB-231 cells. Luciferase activity, as a reflection of % cell kill, was measured using a Bio-Tek microplate luminescence reader. Results: Significant cytotoxicity was notably observed when MDA-MB-231 cells were co-cultured with neutrophils purified from patients with invasive tumors. Pre-operative breast cancer patients (n=21) had a cell kill range of 0-30% (mean = 12.1%), whereas healthy subjects (n=9) had a cell kill range of 0.2-8% (mean = 2.6%), p<0.004. DCIS patients (N=3) had a cell kill range of 3-4% (mean = 2.7). Conclusions: To date, this preliminary work is the first to demonstrate the cytotoxic role of select neutrophils in the peripheral blood of breast cancer patients as contrasted with those from women without breast cancer. Further studies are needed to evaluate the prognostic and therapeutic role of cytotoxic neutrophils.

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