Cancer Research and Treatment

Original Articles

Low Doses of Nonylphenol Promote Growth of Colon Cancer Cells through Activation of ERK1/2 via G Protein‒Coupled Receptor 30: Ming Xie, Jin-Long Liang, Han-Dong Huang, Mai-Jian Wang, Tao Zhang, Xue-Feng Yang; Cancer Res Treat. 2019;51(4):1620-1631. Published online May 15, 2019; DOI: https://doi.org/10.4143/crt.2018.340

Purpose
Nonylphenol (NP) is an endocrine disruptor found in products such as cleaners, plastics, and detergents. It exerts actions similar to endogenous 17β-estradiol (E2) and is reported to influence various cancers. However, its role in colon cancer remains elusive.
Materials and Methods
Colon cancer cell lines COLO 205 and SW480 were employed in our study. The cells were treated with NP or E2 followed by measurement of apoptosis and proliferation using flow cytometry and MTT assays, respectively. G protein–coupled estrogen receptor 30 (GPR30) expression was visualized using immunofluorescence and Western blot. To investigate the underlying mechanism, the expression levels of GPR30, p-protein kinase A (PKA), c-myc, cyclin D1, and ERK1/2 were analyzed using Western blot. Meanwhile, the GPR30 antagonist G15 was utilized to validate the role of GPR30 in colon cancer progression. Finally, the effect of a GPR30 inhibitor on tumor growth was determined in vivo using tumor xenograft mouse models.
Results
NP facilitated the proliferation of colon cancer cells and induced apoptosis failure in vitro. Western blot revealed increased GPR30 expression levels in response to NP treatment. Cyclin D1, p-PKA, c-myc, and proliferating cell nuclear antigen, proteins that regulate the cell cycle, were all upregulated by NP, and NP-mediated ERK1/2 activation and subsequent cell proliferation were abrogated by the GPR30 inhibitor G15. Moreover, colon cancer mice that received G15 administration demonstrated impaired tumor growth in vivo.
Conclusion
Low dose NP promotes the growth of colon tumors through GPR30-mediated activation of ERK1/2 signaling.

Citations

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Role of sex steroids in colorectal cancer: pathomechanisms and medical applications
Jianglan Wu
American Journal of Cancer Research.2024; 14(7): 3200. CrossRef
17β-estradiol in colorectal cancer: friend or foe?
Zihong Wu, Chong Xiao, Jiamei Wang, Min Zhou, Fengming You, Xueke Li
Cell Communication and Signaling.2024;[Epub] CrossRef
Magnetic nanoparticles for eliminating endocrine-disrupting compounds in water treatment – a quantitative systematic analysis
Juliana Guimarães, Igor Taveira, Thuane Mendes Anacleto, Alex Enrich-Prast, Fernanda Abreu
Frontiers in Environmental Science.2024;[Epub] CrossRef
Implications of estrogen and its receptors in colorectal carcinoma
Plabon Kumar Das, Joti Saha, Suja Pillai, Alfred K.‐Y. Lam, Vinod Gopalan, Farhadul Islam
Cancer Medicine.2023; 12(4): 4367. CrossRef
Endocrine-Disrupting Chemicals and Disease Endpoints
Changhwan Ahn, Eui-Bae Jeung
International Journal of Molecular Sciences.2023; 24(6): 5342. CrossRef
Hsp27, a potential EcR target, protects nonylphenol-induced cellular and organismal toxicity in Drosophila melanogaster
Shiwangi Dwivedi, Leonard Clinton D'Souza, Nidhi Ganesh Shetty, Shamprasad Varija Raghu, Anurag Sharma
Environmental Pollution.2022; 293: 118484. CrossRef
Effect of nonylphenol on the colonic mucosa in rats and intervention with zinc-selenium green tea (Camellia sinensis)
Shixu Li, Mucong Zheng, Xuefeng Yang, Jianling Zhang, Jie Xu, Jie Yu
Toxicology Research.2022; 11(1): 122. CrossRef
Nonylphenol regulates TL1A through the AhR/HDAC2/HNF4α pathway in endothelial cells to promote the angiogenesis of colorectal cancer
Tao Zhang, Wei-Wei Ning, Jie Zhang, Fu-Jian Xu, Xing-Qin Wang, Zheng-Biao Li, Ming Xie
Toxicology and Applied Pharmacology.2022; 436: 115854. CrossRef
Effects of subchronic exposure of nonylphenol on the expression of immune-related factors and estrogen receptors in the spleen of rats
Xiangjun Fu, Jie Xu, Chengyu Ni, Degang Yu, Haibo Wang, Pan Wang, Man Luo, Jie Yu
Environmental Sciences Europe.2022;[Epub] CrossRef
Mechanism of nonylphenol induced gastric inflammation through NF-κB/NLRP3 signaling pathway
Jie Xu, Shixu Li, Xuefeng Yang, Haibo Wang, Lina Ma, Yuan Shen, Jie Yu
Toxicology.2022; 479: 153294. CrossRef
Nonylphenol Promoted Epithelial–Mesenchymal Transition in Colorectal Cancer Cells by Upregulating the Expression of Regulator of Cell Cycle
Nian-jie Zhang, Yuanwei Zhang, Shuo Yin, Du-ji Ruan, Nian He, Xu Chen, Xue-feng Yang
Chemical Research in Toxicology.2022; 35(9): 1533. CrossRef
Co-exposure to BPA and DEHP enhances susceptibility of mammary tumors via up-regulating Esr1/HDAC6 pathway in female rats
Xuan Zhang, Cheng Cheng, Guopei Zhang, Mingyang Xiao, Liuli Li, Shengwen Wu, Xiaobo Lu
Ecotoxicology and Environmental Safety.2021; 221: 112453. CrossRef
Coiled-Coil Domain Containing 80 Suppresses Nonylphenol-Induced Colorectal Cancer Cell Proliferation by Inhibiting the Activation of ERK1/2
Jing Wang, Yuan-wei Zhang, Nian-jie Zhang, Shuo Yin, Du-ji Ruan, Nian He, Xu Chen, Xue-feng Yang
Frontiers in Cell and Developmental Biology.2021;[Epub] CrossRef
Residential proximity to industrial pollution sources and colorectal cancer risk: A multicase-control study (MCC-Spain)
Javier García-Pérez, Nerea Fernández de Larrea-Baz, Virginia Lope, Antonio J. Molina, Cristina O'Callaghan-Gordo, María Henar Alonso, Marta María Rodríguez-Suárez, Benito Mirón-Pozo, Juan Alguacil, Inés Gómez-Acebo, Nieves Ascunce, Mercedes Vanaclocha-Esp
Environment International.2020; 144: 106055. CrossRef

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Prognostic Role of Rb, p16, Cyclin D1 Proteins in Soft Tissue Sarcomas: Byoung Yong Shim, Jinyoung Yoo, Yeon-Soo Lee, Young Sun Hong, Hoon-Kyo Kim, Jin-Hyoung Kang; Cancer Res Treat. 2010;42(3):144-150. Published online September 30, 2010; DOI: https://doi.org/10.4143/crt.2010.42.3.144

Abstract PDF PubReader ePub

Purpose

The aim of this study was to determine the expressions of Rb, p16, and cyclin D1 in soft tissue sarcomas, and we also wanted to identify the prognostic factors according to the clinicalpathologic features.

Materials and Methods

We reviewed the charts and radiographic films of 66 sarcoma patients. Tissue samples were collected from these patients. Immunochemistry was performed using formalin-fixed, paraffin-embedded tissue samples to examine the expressions of p16, Rb, and cyclin D1 proteins.

Results

The median duration of overall survival was 47.8 months (range, 20.0 to 70.7 months) and the 5 years survival rate was 39%. As for the correlation between the degree of immunohistochemical staining for Rb protein and the histological tumor grades, there was a significant difference with a p-value of 0.019. However, no significant correlation was shown for p16 and cyclin D1. The overall survival duration of the Rb negative group (staining cell <20%) and the heterogeneous group (cell staining 20 to 80%) was 53.5±6.6 months and the overall survival duration of the Rb homogeneous group was 18.3±6.4 months, and there was a significant difference with a p-value of 0.016. However, no significant difference was shown between the survival rate according to the p16 and cyclin D1 expressions. On the multivariate analysis that was done with Rb, p16, the tumor size, grade and site, and patient age, the Rb gene expression was the most significant independent prognostic factor with a risk ratio of 3.01 (p=0.04).

Conclusion

The expression of Rb protein was correlated with the histologic grade and overall survival of patients with soft tissue sarcomas.

Citations

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Immunohistochemical Expression of p16 and CDK4 in Soft Tissue Tumors
Mala Sagar, Rita Yadav, Pankaj Deval, Madhu Kumar, Malti K Maurya, Sumaira Qayoom
Cureus.2023;[Epub] CrossRef
Carcinosarcoma, a Rare Malignant Neoplasm of the Pancreas
Jaffar Khan, Liang Cheng, Michael G. House, Shunhua Guo
Current Oncology.2021; 28(6): 5295. CrossRef
Co-expression of MDM2 and CDK4 in transformed human mesenchymal stem cells causes high-grade sarcoma with a dedifferentiated liposarcoma-like morphology
Yu Jin Kim, Mingi Kim, Hyung Kyu Park, Dan Bi Yu, Kyungsoo Jung, Kyoung Song, Yoon-La Choi
Laboratory Investigation.2019; 99(9): 1309. CrossRef
Prognostic significance of p16INK4a alteration in soft tissue sarcomas: A meta-analysis
Gang Lin, Yue Lou
Indian Journal of Cancer.2017; 54(3): 580. CrossRef
GATA3 Expression Is a Poor Prognostic Factor in Soft Tissue Sarcomas
Toshiaki Haraguchi, Hiroaki Miyoshi, Koji Hiraoka, Shintaro Yokoyama, Yukinao Ishibashi, Toshihiro Hashiguchi, Koutaro Matsuda, Tetsuya Hamada, Takahiro Okawa, Naoto Shiba, Koichi Ohshima, Ichiro Aoki
PLOS ONE.2016; 11(6): e0156524. CrossRef
Sarcoma spreads primarily through the vascular system: are there biomarkers associated with vascular spread?
Elisabetta Pennacchioli, Giulio Tosti, Massimo Barberis, Tommaso M. De Pas, Francesco Verrecchia, Claudia Menicanti, Alessandro Testori, Giovanni Mazzarol
Clinical & Experimental Metastasis.2012; 29(7): 757. CrossRef

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Cyclin D1 Overexpression, p16 Loss, and pRb Inactivation Play a Key Role in Pulmonary Carcinogenesis and have a Prognostic Implication for the Long-term Survival in Non-small Cell Lung Carcinoma Patients: Na-Hye Myong; Cancer Res Treat. 2008;40(2):45-52. Published online June 30, 2008; DOI: https://doi.org/10.4143/crt.2008.40.2.45

Abstract PDF PubReader ePub

Purpose

We investigated the immunoexpressions of cyclin D1, cyclin-dependent kinase inhibitor p16 and phosphorylated retinoblastoma (p-pRb) proteins in non-small cell lung carcinoma (NSCLC) to demonstrate their key roles in tumorigenesis, their relationship with the clinicopathologic factors, and their prognostic influences on the long-term survival.

Materials and Methods

115 surgically resected NSCLCs were immunohistochemically stained for the G₁/S cell cycle proteins, with using a tissue microarray. The correlation between their immunoexpressions and the clinicopathologic prognostic factors, their inter-relationships and their single or combined effects on the long-term survival (over 5 years) were statistically analyzed by SPSS15.0.

Results

Loss of p16 was found in 75% of the cases and cyclin D1 overexpression and phosphorylated pRb (p-pRb) were found in 64% and 46%, respectively. Cyclin D1 overexpression was correlated with the p16 loss and pRb inactivation by phosphorylation. The p16 loss was tightly associated with p-pRb. The Kaplan-Meier survival curves disclosed that the cyclin D1-positive group and the p16-negative group showed a rapid decline of survival at the point of about 5 years after surgery and thereafter. The combined actions of cyclin D1 overexpression, loss of p16 and pRb inactivation tended to have an adverse influence on the prolonged survival.

Conclusions

The observation that cyclin D1 overexpression, p16 loss and pRb inactivation were largely found in NSCLCs suggests that they play an important role in pulmonary carcinogenesis. Also, their inverse or positive correlations indicate that the G₁/S cell cycle proteins may act alternatively or synergistically on the mechanisms by which tumor cells escape the G₁ restriction point. Finally, their solitary or combined actions might have a long-term effect on the survival.

Citations

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Human Papillomavirus Is Rare and Does Not Correlate with p16INK4A Expression in Non-Small-Cell Lung Cancer in a Jordanian Subpopulation
Ola Abu Al Karsaneh, Arwa Al Anber, Sahar AlMustafa, Hussien AlMa’aitah, Batool AlQadri, Abir Igbaria, Rama Tayem, Mustafa Khasawneh, Shaima Batayha, Tareq Saleh, Mohammad ALQudah, Maher Sughayer
Medicina.2024; 60(4): 660. CrossRef
RB1: governor of the cell cycle in health and disease—a primer for the practising pathologist
Fleur Cordier, David Creytens
Journal of Clinical Pathology.2024; 77(7): 435. CrossRef
The Intersection of Genetic and Molecular Biology in Oral Potentially Malignant Disorders: Identifying Key Biomarkers and Pathways for Clinical Intervention
Hema Shree K
International Journal of Histopathological Interpretation.2024; 13(2): 1. CrossRef
Effects of the p16/cyclin D1/CDK4/Rb/E2F1 pathway on aberrant lung fibroblast proliferation in neonatal rats exposed to hyperoxia
Shimeng Zhao, Zhiguang Chen, Shuang Han, Hongmin Wu
Experimental and Therapeutic Medicine.2021;[Epub] CrossRef
Co-Occurrence of Differentiated Thyroid Cancer and Second Primary Malignancy: Correlation with Expression Profiles of Mismatch Repair Protein and Cell Cycle Regulators
Chih-Yi Liu, Ching-Shui Huang, Chi-Cheng Huang, Wei-Chi Ku, Hsing-Yu Shih, Chi-Jung Huang
Cancers.2021; 13(21): 5486. CrossRef
Ultrasound-Targeted Microbubble Destruction Mediated si-CyclinD1 Inhibits the Development of Hepatocellular Carcinoma via Suppression of PI3K/AKT Signaling Pathway

Wei Yan, Li Cheng, Dongmei Zhang
Cancer Management and Research.2020; Volume 12: 10829. CrossRef
Loss of pRB in Conjunctival Squamous Cell Carcinoma: A Predictor of Poor Prognosis
Sheetal Chauhan, Seema Sen, Anjana Sharma, Seema Kashyap, Radhika Tandon, Neelam Pushker, Murugesan Vanathi, Shyam S. Chauhan
Applied Immunohistochemistry & Molecular Morphology.2018; 26(6): e70. CrossRef
Bronchial-pulmonary adenocarcinoma subtyping relates with different molecular pathways
Vítor Sousa, Bruno Bastos, Maria Silva, Ana Maria Alarcão, Lina Carvalho
Revista Portuguesa de Pneumologia (English Edition).2015; 21(5): 259. CrossRef
Mechanisms of environmental chemicals that enable the cancer hallmark of evasion of growth suppression
Rita Nahta, Fahd Al-Mulla, Rabeah Al-Temaimi, Amedeo Amedei, Rafaela Andrade-Vieira, Sarah N. Bay, Dustin G. Brown, Gloria M. Calaf, Robert C. Castellino, Karine A. Cohen-Solal, Anna Maria Colacci, Nichola Cruickshanks, Paul Dent, Riccardo Di Fiore, Stefa
Carcinogenesis.2015; 36(Suppl 1): S2. CrossRef
Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead
William H. Goodson, Leroy Lowe, David O. Carpenter, Michael Gilbertson, Abdul Manaf Ali, Adela Lopez de Cerain Salsamendi, Ahmed Lasfar, Amancio Carnero, Amaya Azqueta, Amedeo Amedei, Amelia K. Charles, Andrew R. Collins, Andrew Ward, Anna C. Salzberg, An
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Prognostic significance of WNT and hedgehog pathway activation markers in cancer of unknown primary
George Fotopoulos, Anna Gousia, Eleni Bareta, Epameinondas Koumpis, Sofia Chrisafi, Matthaios Bobos, Vassiliki Malamou‐Mitsi, George Fountzilas, Nicholas Pavlidis, George Pentheroudakis
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WITHDRAWN: Bronchial-pulmonary adenocarcinoma subtyping relates with different molecular pathways
Vítor Sousa, Bruno Bastos, Maria Silva, Ana Maria Alarcão, Lina Carvalho
Revista Portuguesa de Pneumologia.2014;[Epub] CrossRef
Association between cyclin D1 G870A polymorphism and cervical cancer risk: a cumulative meta-analysis involving 2,864 patients and 3,898 controls
Yuan-Yuan Hu, Rong Zheng, Chong Guo, Yu-Ming Niu
Diagnostic Pathology.2014;[Epub] CrossRef
Chordoma: the entity
Youssef Yakkioui, Jacobus J. van Overbeeke, Remco Santegoeds, Manon van Engeland, Yasin Temel
Biochimica et Biophysica Acta (BBA) - Reviews on Cancer.2014; 1846(2): 655. CrossRef
RB1 in cancer: Different mechanisms of RB1 inactivation and alterations of pRb pathway in tumorigenesis
Riccardo Di Fiore, Antonella D'Anneo, Giovanni Tesoriere, Renza Vento
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Prognostic and Predictive Value of Cell Cycle Deregulation in Non-Small-Cell Lung Cancer
William Sterlacci, Michael Fiegl, Alexandar Tzankov
Pathobiology.2012; 79(4): 175. CrossRef
Expression of Cyclin D1 Is Associated with β-Catenin Expression and Correlates with Good Prognosis in Colorectal Adenocarcinoma
Kyu Yun Jang, Yo Na Kim, Jun Sang Bae, Myoung Ja Chung, Woo Sung Moon, Myoung Jae Kang, Dong Geun Lee, Ho Sung Park
Translational Oncology.2012; 5(5): 370. CrossRef
A Comprehensive Analysis of p16 Expression, Gene Status, and Promoter Hypermethylation In Surgically Resected Non-small Cell Lung Carcinomas
William Sterlacci, Alexandar Tzankov, Lothar Veits, Bettina Zelger, Michel P. Bihl, Anja Foerster, Florian Augustin, Michael Fiegl, Spasenija Savic
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Expression of p16 in non-small cell lung cancer and its prognostic significance: A meta-analysis of published literatures
Jinlong Tong, Xinchen Sun, Hongyan Cheng, Di Zhao, Jun Ma, Qing Zhen, Yuandong Cao, Huiping Zhu, Jianling Bai
Lung Cancer.2011; 74(2): 155. CrossRef

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The Role of E-cadherin/β-catenin Complex and Cyclin D1 in Head and Neck Squamous Cell Carcinoma: Nam Yong Do, Sung Yong Park, Sung Chul Lim; Cancer Res Treat. 2004;36(1):72-78. Published online February 29, 2004; DOI: https://doi.org/10.4143/crt.2004.36.1.72

Abstract PDF PubReader ePub

Purpose

To determine the relationship between expression pattern of E-cadherin, β-catenin and cyclin D1, and clinicopathologic parameters in patients with head and neck squamous cell carcinomas (HNSCC).

Materials and Methods

The authors evaluated the immunohistochemical expression pattern of E-cadherin, β-catenin in relationship with cyclin D1 overexpression, degree of histologic differentiation, clinical stage, and nodal status in 146 head and neck squamous cell carcinomas (HNSCC). The authors also evaluated the expression of E-cadherin/β-catenin complex, E-cadherin/cyclin D1, and β-catenin/cyclin D1 double staining with confocal laser scanning microscope.

Results

Aberrant expressions in 78% of E-cadherin, 77% of β-catenin, and 69% of cyclin D1 in the HNSCC were observed. There was correlation of aberrant expression of E-cadherin and nodal status. Cyclin D1 overexpression was also correlated to clinical stage and nodal status. Significant relation was observed between E-cadherin and β-catenin expression patterns. Co-expression of E-cadherin and β-catenin was significantly detected. However, there was no correlation of cyclin D1 overexpression with E-cadherin or β-catenin expression patterns.

Conclusion

These results suggest that aberrant expression of E-cadherin, E-cadherin/β-catenin complex, and cyclin D1 may be involved in clinical stage and/or nodal status, and analysis of the pattern of E-cadherin, cyclin D1, and E-cadherin/β-catenin complex may be good prognostic marker of HNSCC.

Citations

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Pilomatrix carcinoma of the right postauricular region: A case report and literature review
Shabiah Martin, Jana DeJesus, Ann Jacob, Teah Qvavadze, Claudio Guerrieri, Rachel Hudacko, Thaddeus Boucree
International Journal of Surgery Case Reports.2019; 65: 284. CrossRef
Role of E-cadherin and cyclin D1 as predictive markers of aggression and clonal expansion in head and neck squamous cell carcinoma
Khushdeep Shergill, Arijit Sen, Hari Janardanan Pillai
Journal of the Korean Association of Oral and Maxillofacial Surgeons.2018; 44(4): 182. CrossRef
Prognostic Significance of Cyclin D1 and E-cadherin Expression in Laryngeal Squamous Cell Carcinoma
Rehab Allah Ahmed, Abd El-Aty Shawky, Rasha Hamdy Hamed
Pathology & Oncology Research.2014; 20(3): 625. CrossRef

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Interrelation of Cyclin D1, Cyclin E, and p27Kip1 Expression on Tissue Arrays of Breast Cancer: Se Hwan Han, Kyeong Mee Park, Byung Noe Bae, Suk Yong Ryu, Ki Hwan Kim, Hong Joo Kim, Young Duck Kim, Hong Yong Kim; Cancer Res Treat. 2002;34(5):388-393. Published online October 31, 2002; DOI: https://doi.org/10.4143/crt.2002.34.5.388

Abstract PDF

PURPOSE
To evaluate the clinical impact of the altered expression of cell cycle regulators in stage I and II breast cancers.
MATERIALS AND METHODS
The interaction between cyclin D1/E and p27Kip1 expressions were analyzed using tissue microarray (TMA) technology in 133 breast cancers. Data from the immunohistochemical assays of 3 molecules were merged, and analyzed, with a Ki67 labeling index of the same tumors.
RESULTS
Cyclin D1 was expressed in 72 breast carcinomas (54.1%) and cyclin E in 60 (45.1%) out of the 133 breast carcinomas. Expressions of cyclin D1 and cyclin E were inversely related to each other, and significantly associated with the estrogen receptor (ER) expression and differentiation of the breast carcinoma. The expression of cyclin E was significantly decreased in tumors expressing cyclin D1 (p=0.022). There was a trend for cyclin D1 expression to increase in tumors expressing p27Kip1 (p=0.053), but the expression of cyclin E did not correlate with p27Kip1 expression. The Ki67 labeling index was markedly increased in tumors expressing cyclin E, whereas it was significantly decreased in the cyclin D1 or p27Kip1 expressing-tumors. From survival analysis, cyclin E expression was the only significant variable for the prediction of poor survival.
CONCLUSION
The abnormal expressions of cell cycle regulatory molecules are prevalent, and interrelated with each other in breast cancer. Integration of TMA technology allowed a high-throughput analysis for correlating molecular the in situ findings, with the clinico-pathologic information. Among the three molecules studied, the cyclin E had a prognostic implication for stage I and II breast cancer.

Citations

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Novel insights into biomarkers of progression in Desmoid tumor
Baiqi Liu, Zefang Sun, Rui Zhou, Dingcheng Shen, Shuai Zhu, Lu Chen, Gengwen Huang
Frontiers in Oncology.2023;[Epub] CrossRef

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Expression of G1/S Phase Checkpoint Proteins in Breast Carcinoma: Relationship to Clinicopathologic Factors andSurvival Rate: Mi Ja Lee; Cancer Res Treat. 2002;34(4):268-273. Published online August 31, 2002; DOI: https://doi.org/10.4143/crt.2002.34.4.268

Abstract PDF: The retinoblastoma protein (pRb)/cyclin D1/ p16 pathway plays a critical role in controlling the progression from G1 to S phase of the cell cycle. Abnormal expression of the individual components of the pathway has been reported in many human cancers, including the breast. Our aim was to investigate the role of this pathway in tumorigenesis and tumor progression, and to evaluate the value of these oncoproteins as potential prognostic factors in breast cancer.
MATERIALS AND METHODS
We examined the significance of the p16, pRb, and cyclin D1 expression in 128 cases of invasive breast carcinomas using immunohistochemistry on formalin fixed, paraffin sections. The results correlated with the survival rate and clinicopathologic variables, including age, histologic grade, lymph node status, tumor size, estrogen receptor (ER) and progesterone receptor (PR) content. The negative finding for nuclear staining for pRb and p16 were defined as abnormal.
RESULTS
Abnormal expression of the p16 and pRb were seen in 21% and 43% of tumors, respectively. There was a significant inverse relationship between the p16 and pRb expressions. There was no association between the p16 staining and any other parameters, including survival rate, cyclin D1, or clinicopathologic variables. Surprisingly, there was a trend for pRb positive tumors to be grade III ductal carcinomas. Cyclin D1 positivity was noted in 46% of cases. The expression of cyclin D1 protein was significantly higher in lower histologic grades, and with higher ER and PR expressions.
CONCLUSION
These findings suggest the p16 may be negatively regulated by the pRb, and that cyclin D1 is involved in the tumor progression in well-differentiated tumors and could be an ER and PR related protein. In a Cox multivariate analysis, the p16, pRb, and cyclin D1 were not independent predictors of patient outcome.

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