Cyclin D1 expression in triple-negative breast cancer with new treatment implications

Volume 1, Issue 1, October 2016     |     PP. 49-57      |     PDF (127 K)    |     Pub. Date: October 15, 2016
DOI:    447 Downloads     5705 Views  


Paul H. Hartel, MD, Davis Medical Center of Davis Health System, Elkins, West Virgini;West Virginia School of Medicine, Morgantown, West Virginia;West Virginia School of Osteopathic Medicine, Lewisburg, West Virginia.
Donald R. Fleming, MD, Davis Medical Center of Davis Health System, Elkins, West Virgini;West Virginia School of Medicine, Morgantown, West Virginia;West Virginia School of Osteopathic Medicine, Lewisburg, West Virginia.

While targeted therapies are available for breast cancer patients whose tumors express ER, PR, or show HER-2 overexpression, no such treatment exists for “triple-negative” cases. As immunohistiochemistry (IHC) expression of Cyclin D1 has been shown concordant with Cyclin D1 gene amplification, we evaluated Cyclin D1 IHC expression in 25 cases of triple-negative invasive ductal carcinoma to clarify its relationship with clinical and pathologic parameters. Twenty-six invasive carcinomas negative for ER, PR, and HER-2 were reviewed. Clinical information, including treatment response, was gleaned from patient records. Tumors were morphologically reviewed and Cyclin D1 IHC applied using BCL-1. Chi square and t-test statistical analyses were performed. Patients were female and had a mean age of 59 years. Tumors were invasive ductal carcinomas of no special type, Nottingham grade 1, 2 and 3. All tumors showed Cyclin D1 expression from light and focal staining to focal intense staining. Patients with tumors showing intense BCL-1 staining had larger tumors with more capillary/lymphatic invasion and lymph node metastases and were less likely to respond to treatment. Cyclin D1 expression may serve as a marker for more biologically aggressive triple-negative breast cancer. These tumors may respond to targeted therapy that down-regulates Cyclin D1 amplification. Further research with larger sample sizes is needed.

triple negative, breast cancer, invasive ductal carcinoma, cyclin D1, immunohistochemistry, personalized medicine

Cite this paper
Paul H. Hartel, MD, Donald R. Fleming, MD, Cyclin D1 expression in triple-negative breast cancer with new treatment implications , SCIREA Journal of Clinical Medicine. Volume 1, Issue 1, October 2016 | PP. 49-57.


[ 1 ] Thike AA, Iqbal J, Cheok PY, Chong AP, Tse GM, Tan B, Tan P, Wong NS, Tan PH.Triple negative breast cancer: outcome correlation with immunohistochemical detection of basal markers. Am J Surg Pathol. 2010 Jul;34(7):956-64.
[ 2 ] Bauer KR, Brown M, Cress RD, et al. Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: a population-based study from the California Cancer Registry. Cancer 2007;109:1721–1728.
[ 3 ] Rebecca Dent, Maureen Trudeau, Kathleen I. Pritchard, Wedad M. Hanna,Harriet K. Kahn, Carol A. Sawka, Lavina A. Lickley, Ellen Rawlinson,Ping Sun and Steven A. Narod. Triple-Negative Breast Cancer: Clinical Features and Patterns of Recurrence. Clin Cancer Res. 2007 Aug (13);4429
[ 4 ] Finn RS1, Bengala C, Ibrahim N, Roché H, Sparano J, Strauss LC, Fairchild J, Sy O, Goldstein LJ. Dasatinib as a single agent in triple-negative breast cancer: results of an open-label phase 2 study. Clin Cancer Res. 2011 Nov 1;17(21):6905-13.
[ 5 ] Finn RS1, Dering J, Ginther C, Wilson CA, Glaspy P, Tchekmedyian N, Slamon DJ. Dasatinib, an orally active small molecule inhibitor of both the src and abl kinases, selectively inhibits growth of basal-type/"triple-negative" breast cancer cell lines growing in vitro. Breast Cancer Res Treat. 2007 Nov;105(3):319-26.
[ 6 ] Withers DA, Harvey RC, Faust JB, Melnyk O, Carey K, Meeker TC Characterization of a candidate bcl-1 gene. Mol Cell Biol. 1991 Oct;11(10):4846-53.
[ 7 ] Fracchiolla NS1, Pruneri G, Pignataro L, Carboni N, Capaccio P, Boletini A, Buffa R, Neri A. Molecular and immunohistochemical analysis of the bcl-1/cyclin D1 gene in laryngeal squamous cell carcinomas: correlation of protein expression with lymph node metastases and advanced clinical stage. Cancer. 1997 Mar 15;79(6):1114-21.
[ 8 ] Livasy CA, Karaca G, Nanda R, Tretiakova MS, Olopade OI, Moore DT, Perou CM. Phenotypic evaluation of the basal-like subtype of invasive breast carcinoma. Mod Pathol 2006;19:264–271.
[ 9 ] Fulford LG, Easton DF, Reis-Filho JS, Sofronis A, Gillett CE, Lakhani SR, Hanby A. Specific morphological features predictive for the basal phenotype in grade 3 invasive ductal carcinoma of breast. Histopathology 2006;49:22–34.
[ 10 ] Turner NC, Reis-Filho JS, Russell AM, Springall RJ, Ryder K, Steele D, Savage K, Gillett CE, Schmitt FC, Ashworth A, Tutt AN. BRCA1 dysfunction in sporadic basal-like breast cancer. Oncogene 2007;26:2126–2132.
[ 11 ] Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, Hernandez-Boussard T, Livasy C, Cowan D, Dressler L, Akslen LA, Ragaz J, Gown AM, Gilks CB, van de Rijn M, Perou CM. Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res. 2004 Aug 15;10(16):5367-74.
[ 12 ] Cheang MC1, Voduc D, Bajdik C, Leung S, McKinney S, Chia SK, Perou CM, Nielsen TO. Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype. Clin Cancer Res 2008;14:1368–1376.
[ 13 ] Fulford LG1, Reis-Filho JS, Ryder K, Jones C, Gillett CE, Hanby A, Easton D, Lakhani SR. Basal-like grade III invasive ductal carcinoma of the breast: patterns of metastasis and long-term survival. Breast Cancer Res 2007;9:R4.
[ 14 ] Reis-Filho JS1, Pinheiro C, Lambros MB, Milanezi F, Carvalho S, Savage K, Simpson PT, Jones C, Swift S, Mackay A, Reis RM, Hornick JL, Pereira EM, Baltazar F, Fletcher CD, Ashworth A, Lakhani SR, Schmitt FC. EGFR amplification and lack of activating mutations in metaplastic breast carcinomas. J Pathol 2006;209:445–453.
[ 15 ] Rakha E, Ellis I, Reis-Filho J. Are triple-negative and basal-like breast cancer synonymous? Clin Cancer Res 2008;14:618; author reply 618–619.
[ 16 ] Reis-Filho JS1, Savage K, Lambros MB, James M, Steele D, Jones RL, Dowsett M. Cyclin D1 protein overexpression and CCND1 amplification in breast carcinomas: an immunohistochemical and chromogenic in situ hybridisation analysis. Mod Pathol 2006;19:999–1009.
[ 17 ] Subhawong AP, Subhawong T, Nassar H, Kouprina N, Begum S, Vang R, Westra WH, Argani P. Most basal-like breast carcinomas demonstrate the same Rb−/p16+ immunophenotype as the HPV-related poorly differentiated squamous cell carcinomas which they resemble morphologically. Am J Surg Pathol 2009;33:163–175.
[ 18 ] Thike AA, Cheok PY, Jara-Lazaro AR, Tan B, Tan P, Tan PH. Triple-negative breast cancer: clinicopathological characteristics and relationship with basal-like breast cancer.Mod Pathol. 2010 Jan;23(1):123-33.
[ 19 ] Gazinska P, Grigoriadis A, Brown JP, Millis RR, Mera A, Gillett CE, Holmberg LH, Tutt AN, Pinder SE.Comparison of basal-like triple-negative breast cancer defined by morphology, immunohistochemistry and transcriptional profiles. Mod Pathol. 2013 Jul;26(7):955-66.
[ 20 ] Parker JS, Mullins M, Cheang MC, Leung S, Voduc D, Vickery T, Davies S, Fauron C, He X, Hu Z, Quackenbush JF, Stijleman IJ, Palazzo J, Marron JS, Nobel AB, Mardis E, Nielsen TO, Ellis MJ, Perou CM, Bernard PS. Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol. 2009 Mar 10;27(8):1160-7.