The HER-2/neu (C-erbB-2) gene is localised to chromosome 17q and encodes a transmembrane tyrosine kinase receptor protein that is a member of the epidermal growth factor receptor family. Slamon et. al. were the first authors to find a strong and highly statistically significant correlation between the degree of gene amplification and both time to disease relapse and survival[5]. Previous studies have shown the prognostic and predictive value of HER-2/neu overexpression in node positive breast cancer[6,7,8] and for metastatic disease[9,10].
Trastuzumab is a humanized antibody against the external domain of HER-2/ neu that presents antitumoral activity[11]. Trastuzumab improves response rates, time to progression and even survival when used alone or added to chemotherapy in metastatic breast cancer[12]. It is also active as a single agent and reduces the risk of recurrence and mortality in patients with early-stage breast cancer[13-15]. The interesting point of such a specific treatment is that only those tumors that overexpress HER-2/neu benefit from such therapy. The determination of HER-2/ neu in breast cancer is very important as it has significant benefits and some side effects like cardiotoxicity[16]. Overexpression of HER-2/neu is most commonly caused by amplification of the HER-2/neu gene, which results in increased HER-2/neu mRNA levels and concomitant overexpression of the HER-2/neu receptor on the tumor cell surface. There is no “gold standard” for HER-2/neu testing but immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) are the most commonly used methods. In addition, chromogenic in situ hybridization and silver in situ hybridization has recently been validated as alternatives to FISH.
Early studies suggested that as many as 30% of breast cancers have HER-2/neu overexpression[17]. However, recent studies showed lower results around 20%[18-20]. The American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) convened an expert panel and recommended a new HER-2/neu testing guideline in 2007 to decrease discordant results[12].
HER-2/neu overexpression has been correlated with several poor prognostic paramaters. They are more likely to be hormone-receptor negative and have higher tumour grade[3,7,21]. The inverse association between HER-2/neu and hormone receptors has been linked with the fact that estrogens suppress HER-2/neu through the ER[22]. One recent report showed that this inverse association differs in different age groups[23]. Tumor grade, as an important predictor for HER-2/neu overexpression shows an association with hormone receptor expression that differs between young and older women and this may be reflected with an age-related association between hormone receptors and HER-2/neu[24-25].
Taken together, the aim of our study was to better understand the relationship between HER-2/neu status and other prognostic factors like age, tumour grade, ER and PR receptor status by comparing the results of immunohistochemistry and FISH in invasive female breast carcinomas at our institution.
Immunohistochemistry
From all cases a set of 4 micrometer-thick paraffin sections
were cut and stained for ER (Novocastra-Clone 6 F 11), PR
(Neomarkers- Clone SP 2) and HER-2/neu (Novocastra-
Clone 10 A 7) antibodies by using microwave for antigen
retrieval. The staining for ER and PR was classified as
positive if more than 10% of the tumor cells exhibited
nuclear staining. The HER-2/neu stained slides were scored
on a scale of 0 to 3+ according to the new ASCO/CAP
guideline recommendations. Scoring was done on a 0-3
scale. Strongly positive (3+) was defined as strong complete
membranous staining in more than 30% of the tumor cell
population. Weakly positive (2+) was defined as moderate
membranous staining in more than 10% of tumor cells and
strong complete membranous staining in less than 30%
of tumor cells. 1+ was defined as either weak or barely
perceptible membranous staining in more than 10% of
the tumor cells. 0 was completely negative staining. Scores
of 0 and 1+ were considered as negative for HER2/neu
expression, 3+ as immunopositive, while 2+ was weakly or
borderline positive.
FISH
FISH analysis was performed to all cases. Amplification of
HER-2/neu was evaluated using the Path-Vysion DNA Probe
Kit (nodul 35-161060; Vysis) which uses a dual-color probe
for determining the number of copies of both HER-2/ neu
(orange) and the chromosome 17 centromeres (green). The
kit was used following the manufacturers instructions with
a few minor modifications. Slides containing 4 micrometerthick
paraffin–embedded tissue sections were placed on a
slide warmer overnight at 62°C followed by deparaffinization in Hemo-De, dehydration in 100% ethanol, and drying on a
slide warmer at 45 to 50°C. Slides were then pretreated with
0, 2N hydrochloric acid for 22 minutes, followed by washes
in purified water and immersion in Vysis wash buffer. They
were subsequently immersed in Vysis protease solution at
37°C for 40 minutes, washed in Vysis wash buffer, and dried
on the slide warmer and 10 ml of probe was applied. Slides
are then put in Hybride for 5 minutes at 72°C. They were
then coverslipped, sealed with rubber conent, and placed
in a prewarmed humid incubation chamber at 37°C for 18
to 22 hours. This was followed by immersion in prewarmed
postwash solution at 73°C for 4 minutes. The slides were
air–dried, and a 4;6 – diamidino -2- phenylindole (DAPI)
counterstain was applied.
The scoring system used is described in detail in the manufacturers instructions. In brief, a minimum of 60 nuclei were scored by each of 2 observers using on Olympus BX41 fluorescent microscope with a Chroma filter set (DAPI / spectrum orange / spectrum green triple bandpass) Areas scored were limited to regions of invasive disease as compared with a companion hematoxylin and eosinstained section. The ratio of HER-2/ neu signals (orange) to chromosome 17 centromere signals (green) was determined.
FISH results were than compared to previously stained and evaluated IHC scores to determine how well protein overexpression correlates with gene amplification.
Statistical Analysis
All statistical analyses were performed with the Statistical
Package for the NCSS 2007 version for Windows. The
chi-square test and odds ratio were used to examine
categorical variables and the association between HER-2/
neu overexpression and other clinicopathological factors in
univariate analysis. Logistic regression analysis was used to
evaluate HER-2/neu FISH scores. All statistical tests were
two–sided and p<0.05 was considered significant.
Table I: Clinicopathological features of 100 invasive mammary carcinomas
Table II: Comparison of HER-2/neu immune scores with FISH amplification (p<0.0001)
Figure 1: Score 3+ staining (HER-2/neu, x400).
Figure 2: Score 3+ staining (HER-2/neu, x100).
In women aged ≤45 years, we found an inverse relationship between HER-2/neu overexpression and progesterone receptor, but we found no association within other factors. However, in women aged >45 years, results revealed that ER status, PR status and tumor grade were significantly associated within HER-2/neu amplification.
IHC and FISH are the two FDA-approved methodologies. IHC is by far the most popular and accessible testing modality. It directly detects HER-2/neu protein overexpression and provides very accurate results with advantages including relative ease of performance, rapid turn-around time, and relatively low cost. FISH methodology is quantitatively more precise but also time consuming, technically demanding and more expensive.
FISH methodology theoretically may not be completely concordant with IHC results as it measures HER-2/neu gene amplification and not protein overexpression. HER- 2/neu gene amplification occurs in about 15-25% of breast cancers, where as the interstudy range at HER-2/neu protein overexpression is higher (10-50%)[28–31]. The range of HER-2/neu protein overexpression falls to 15-20% when gene amplification is also present.
In our study, we found good correlation between the IHC and FISH methods (p= 0.0001). None of the cases with score 0 or 1 showed amplification. Twenty five percent of the cases with immune score 2+ showed amplification. Eighty six percent of the cases with immune score 3+ were amplified but 2 cases with immune score 3+ did not show amplification. In the literature, concordance rates between IHC and FISH range from 79% to 100% for 3+ cases[32,33] and between 12% and 36% for 2+ cases[34,35]. Although there is good correlation between HER-2/neu gene amplification and protein overexpression, approximately 5-10%[36] of breast carcinomas overexpress HER-2/neu without amplification and a small undetermined percentage amplify HER-2/neu without overexpression[37]. In the study of Rossi et al, the percentage of cases with HER-2/ neu protein overexpression (3+) and FISH negativity rose to 22%[38]. In the literature it is proposed that these 3+ cases could be due to single copy overexpression of the HER-2/neu gene[39]. These cases are considered clinically similar to the immunohistochemically HER-2/neu negative patients[40].
HER-2/neu amplification in different histological types has been a subject of interest. While some prior studies have reported the absence of a significant association between tumor type and HER-2/neu status[40], other studies have shown that HER-2/neu amplification or overexpression was significantly more likely in infiltrating ductal carcinomas than infiltrating lobular carcinomas. But Hoff et.al.[41] demonstrated that infiltrating ductal carcinomas were significantly more likely to show HER-2/neu amplification than infiltrating lobular carcinomas. In this study, 15 of the 17 amplified cases were of the infiltrating ductal carcinoma type and 2 cases were medullary carcinomas. None of the other types was amplified.
Previous studies have shown a strong correlation between HER-2/neu protein overexpression/amplification and steroid receptor negativity and high tumour grade[1,4,25,27,42]. We also found similar results through all age groups. The relationship between the age of patients and HER-2/neu status and other prognostic factors is another subject of interest. We did not find a significant relationship between HER-2/neu gene amplification and patient age as previous studies[1]. Although Huang et.al. also did not find a statistically significant difference in expression of HER-2/ neu by age ≤45 and > 45 years, they suggested an age related association between ER, PR, tumour grade and HER-2/neu overexpression[22]. Their results suggested that the inverse association between the hormone receptor and HER-2/ neu status only appeared in women aged beyond 45 but not under 45. In this study, we found inverse relationship between PR and HER-2/neu amplification in all age groups. However, we found a relationship between HER-2/neu status with ER negativity and high tumor grade only in women aged beyond 45. Konecny et.al. also found that the relatively low levels of HER-2/neu amplification/overexpression were associated with more marked decreases of PR than of ER[43], because PR expression is linked to a biologically active and functional ER[42-44]. It has been shown that the activation of growth factor receptors such as HER-2/neu can result in direct phosphorylation and activation of ER in an estrogen–independent manner, which may itself be an important mechanism for tamoxifen resistance in addition to the subsequent reduction in hormone receptor levels[45]. However, it appears likely that this reduced expression is not the only mechanism for endocrine resistance in patients with HER-2/neu and that steroid receptors are most likely determined by multiple complex mechanisms, such as phosphorylation of the ER via HER-2/neu activation[46], overexpression of the steroid receptor cofactorA1B1 in HER-2/neu positive tumors[47] and competition between ER and other coregulatory receptor proteins resulting in altered HER-2/neu expression[48].
In our institution, we perform immunohistochemistry for detecting HER-2/neu and hormonal status. In this study, we compared our IHC scores with FISH method and found a significant correlation. In conclusion, we suggest performing FISH only in cases with an IHC score of 2+. Although we have a limited number of patients, we found that mainly PR negativity predicts HER-2/neu overexpression through all age groups. In women beyond the age of 45, there is also a strong correlation between HER-2/neu, ER negativity and tumor grade. A combination of HER-2/neu and histological prognostic factors can help to determine subgroups for more specific treatment protocols.
1) Pinto AE, André S, Pereira T, Nóbrega S, Soares J: C-erbB-2
oncoprotein overexpression identifies a subgroup of estrogen
receptor positive (ER+) breast cancer patients with poor
prognosis. Ann Oncol 2001, 12:525-533 [ Özet ]
2) Huang HJ, Neven P, Drijkoningen M, Paridaens R, Wildiers
H, Van Limbergen E, Berteloot P, Amant F, Christiaens MR,
Vergote I: Association between HER-2 /neu and the progesterone
receptor in oestrogen-dependent breast cancer is age-related.
Breast Cancer Res Treat 2005, 91:81-87 [ Özet ]
3) Ross JS, Fletcher JA: The HER-2 /neu oncogene in breast cancer:
Prognostic factor, predictive factor, and target for therapy.
Oncologist 1998, 3:237-252 [ Özet ]
4) Révillion F, Bonneterre J, Peyrat JP: ERBB2 Oncogene in human
breast cancer and its clinical significance. Eur J Cancer 1998,
34:791-808 [ Özet ]
5) Slamon DJ, Clark GM, Wong SG, Lewin WJ, Ullrich A, McGuire
WL: Human breast cancer: Correlation of relapse and survival
with amplification of the HER 2/ neu oncogene. Science 1987,
235:177-182 [ Özet ]
6) Tandon AK, Clark GM, Chamness GC, Ullrich A, McGuire WL:
HER-2 /neu oncogene protein and prognosis in breast cancer. J
Clin Oncol 1989, 7:1120-1128 [ Özet ]
7) Sjögren S, Inganäs M, Lindgren A, Holmberg L, Bergh J:
Prognostic and predictive value of c-erb-B2 overexpression
in primary breast cancer, alone and in combination with other
prognostic markers. J Clin Oncol 1998, 16:462-469 [ Özet ]
8) Muss HB, Thor AD, Berry DA, Kute T, Liu ET, Cirrincione CT,
Budman DR, Wood WC, Barcos M, Henderson IC: C-erb-B2
expression and response to adjuvant therapy in women with
node-positive early breast cancer. N Engl J Med 1994, 330:
1260-1266 [ Özet ]
9) Cobleigh MA, Vogel CL, Tripathy D, Robert NJ, Scholl S,
Fehrenbacher L, Wolter JM, Paton V, Shak S, Lieberman G,
Slamon DJ: Multinational study of the efficacy and safety of
humanized anti-HER2 overexpressing metastatic breast cancer
that has progressed after chemotherapy for metastatic disease. J
Clin Oncol 1999, 17:2639-2648 [ Özet ]
10) Slamon DJ, Leyland-Jones B, Shak S, Fucks H, Paton V,
Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M,
Baselga J, Norton L: Use of chemotherapy plus a monoclonal
antibody against HER2 for metastatic breast cancer that
overexpresses HER2. N Engl J Med 2001, 344:783-792 [ Özet ]
11) Hudziak RM, Lewis GD, Winget M, Fendly BM, Shepard HM,
Ullrich A: p185HER2 monoclonal antibody has antiproliferative
effects in vitro and sensitizes human breast tumours cells to
tumor necrosis factor. Mol Cell Biol 1989, 9:1165-1172 [ Özet ]
12) Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred
DC, Cote RJ, Dowsett M, Fitzgibbons PL, Hana WM, Langer A,
McShane LM, Paik S, Pegram MD, Perez EA, Pres MF, Rhodes
A, Sturgeon C, Taube SE, Tubbs R, Vance GH, van de Vijver M,
Wheeler TM, Hayes DF: American Society of Clinical Oncology
/ College of American Pathologist guideline recommendations
for human epidermal growth factor receptor 2 testing in breast
cancer. J Clin Oncol 2007, 25:118-145 [ Özet ]
13) Cardoso F, Durbecq V, Larsimont D, Paesmans M, Leroy JY,
Rovas G, Sotiriou C, Renald N, Richard V, Piccart MJ, Di Leo A:
Correlation between complete response to anthracycline-based
chemotherapy and topoisomerase II-alpha gene amplification
and protein overexpression in locally advanced / metastatic breast
cancer. Int J Oncol 2004, 24:201-209 [ Özet ]
14) Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja
V, Asola R, Utriainen T, Kokko R, Hemminki A, Tarkkanen
M, Turpeenniemi-Hujanen T, Jyrkkiö S, Flander M, Helle L,
Ingalsuo S, Johansson K, Jääskeläinen AS, Pajunen M, Rauhala
M, Kaleva-Kerola J, Salminen T, Leinonen M, Elomaa I, Isola J:
Adjuvant docetaxel or vinorelbine with or without trastuzumab
for breast cancer. N Engl J Med 2006, 354:809-820 [ Özet ]
15) Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr,
Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA,
Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel
VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil
SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark
N: Trastuzumab plus adjuvant chemotherapy for operable HER2-
positive breast cancer. N Engl J Med 2005, 353:1673-1684 [ Özet ]
16) Hayes DF, Picard MH: Heart of Darkness: The downside of
trastuzumab. J Clin Oncol 2006, 24: 4056-4058 [ Özet ]
17) Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith
DE, Lewin WJ, Stuart SG, Udove J, Ullrich A, Press MF: Studies
of the HER-2/neu proto-oncogene in human breast and ovarian
cancer. Science 1989, 244:707-712 [ Özet ]
18) Yaziji H, Goldstein LC, Barry TS, Werling R, Hwang H, Ellis
GK, Gralow JR, Livingston RB, Gown AM: HER-2 testing in
breast cancer using paralel tissue-based methods. JAMA 2004,
291:1972-1977 [ Özet ]
19) Owens MA, Horten BC, Da Silva MM: HER2 amplification
ratios by fluorescence in situ hybridization and correlation with
immunohistochemistry in a cohort of 6556 breast cancer tissues.
Clin Breast Cancer 2004, 5:63-69 [ Özet ]
20) Dowsett M, Hanna WM, Kockx M, Penault-Llorca F, Rüschoff
J, Gutjahr T, Habben K, van de Vijver MJ: Standardization of
HER2 testing: Results of an international proficiency-testing ring
study. Mod Pathol 2007, 20, 584-591 [ Özet ]
21) Albain KS, Allred DC, Clark GM: Breast cancer outcome and
predictors of outcome: are there age differentials ? J Natl Cancer
Inst Monogr 1994, 16:35-42 [ Özet ]
22) Russell KS, Hung MC: Transcriptional repression of the neu
proto-oncogene by estrogen stimulated estrogen receptor. Cancer
Res 1992, 52:6624-6629 [ Özet ]
23) Huang HJ, Neven P, Drijkoningen M, Paridaens R, Wildiers H,
Van Limbergen E, Berteloot P, Amant F, Vergote I, Christiaens
MR: Hormone receptors do not predict the HER2 / neu status
in all age groups of women with an operable breast cancer. Ann
Oncol 2005, 16:1755-1761 [ Özet ]
24) Nixon AJ, Neuberg D, Hayes DF, Gelman R, Connolly JL, Schnitt
S, Abner A, Recht A, Vicini F, Harris JR: Relationship of patient
age to pathologic features of the tumor and prognosis for patients
with stage I or II breast cancer. J Clin Oncol 1994, 12:888-894 [ Özet ]
25) Remvikos Y, Magdelenat H, Dutrillaux B: Genetic evolution of
breast cancers. III: age-dependent variations in the correlations
between biological indicators of prognosis. Breast Cancer Res
Treat 1995, 34:25-33 [ Özet ]
26) Greene FL, Page DL, Fleming ID, Fritz AG, Balch CM, Haller
DG, Morrow M. (Eds): American Joint Committee on Cancer
Staging Manual. 6th ed., New York, Springer-Verlag, 2002, 223-
240
27) Sparano JA: Cardiac toxicity of trastuzumab (Herceptin):
Implications for the design of adjuvant trials. Semin Oncol 2001,
28: 20-27 [ Özet ]
28) Pala EE, Zekioğlu O, Özdemir N, Yılmaz R, Kapkaç M:
Comparison of immunohistochemistry and fluorescence in situ
hybridisation for the analysis of HER2/neu and topoisomerase
II-alpha status in human breast cancer. Turk Patoloji Derg 2010,
26:222-229
29) Ferrero-Poüs M, Hacène K, Bouchet C, Le Doussal V, Tubiana-
Hulin M, Spyratos F: Relationship between c-erbB-2 and other
tumor characteristics in breast cancer prognosis. Clin Cancer Res
2000, 6:4745-4754 [ Özet ]
30) Ridolfi RL, Jamehdor MR, Arber JM: HER-2 /neu testing in breast
carcinoma: A combined immunohistochemical and fluorescence
in situ hybridization approach. Mod Path 2000, 13:866-873 [ Özet ]
31) Hana W, Kahn HJ, Trudeau M: Evaluation of HER-2/neu (erbB-
2) status in breast cancer: from bench to bedside. Mod Pathol
1999, 12:827-834 [ Özet ]
32) Lebeau A, Deimling D, Kaltz C, Sendelhofert A, Iff A, Luthardt B,
Untch M, Löhrs U: HER-2 /neu analysis in archival tissue samples
of human breast cancer: Comparison of immunohistochemistry
and fluorescence in situ hybridization. J Clin Oncol 2001, 19:
354-363 [ Özet ]
33) Tubbs RR, Pettay JD, Roche PC, Stoler MH, Jenkins RB, Grogan
TM: Discrepancies in clinical laboratory testing of eligibility for
trastuzumab therapy: Apparent immunohistochemical falsepositives
do not get the message. J Clin Oncol 2001, 19:2714-2721 [ Özet ]
34) Perez EA, Roche PC, Jenkins RB, Reynolds CA, Halling KC, Ingle
JN, Wold LE: HER-2/neu testing in patients with breast cancer:
Poor correlation between weak positivity and gene amplification
by fluorescence in situ hybridization. Mayo Clinic Proc 2002,
77:148-154 [ Özet ]
35) Ridolfi RL, Jamehdor MR, Arber JM: HER-2 / neu testing in breast
carcinoma: A combined immunohistochemical and fluorescence
in situ hybridization approach. Mod Pathol 2000,13:866-873 [ Özet ]
36) Birner P, Oberhuber G, Stani J, Reithofer C, Samonigg H,
Hausmaninger H, Kubista E, Kwasny W, Kandioler-Eckersberger
D, Gnant M, Jakesz R: Evaluation of the United States Food and
Drug Administration-approved scoring and test system of HER-
2 protein expression in breast cancer. Clin Cancer Res 2001,
7:1669-1675 [ Özet ]
37) Pauletti G, Godolphin W, Press MF, Slamon DJ: Detection and
quantitation of HER-2 / neu gene amplification in human breast
cancer archival material using fluorescence in situ hybridization.
Oncogene 1996, 13:63-72 [ Özet ]
38) Rossi E, Ubiali A, Cadei M, Balzarini P, Valagussa E, Lucini L,
Alpi F, Galletti A, Fontana L, Tedoldi C, Grigolato P: HER-2
/ neu in breast cancer: A comparative study between histology,
immunohistochemistry, and moleculer technique (FISH). Appl
Immunohistochem Mol Morphol 2006, 14:127-131 [ Özet ]
39) Uehara T, Kaneko Y, Kanda N, Yamamoto T, Higashi Y, Nomoto
C, Izumo T, Takayama S, Sakurai M: C-erb-B2 and c-erbA-
1(ear-1) gene amplification and c-erb-2 protein expression in
Japanese breast cancers: their relationship to the histology and
other disease parameters. Jpn J Cancer Res 1990, 81:620-624 [ Özet ]
40) Persons DL, Borelli KA, Hsu PH: Quantitation of HER-2 /
neu and c-myc gene amplification in breast carcinoma using
fluorescence in situ hybridization. Mod Pathol 1997, 10: 720-727 [ Özet ]
41) Hoff ER, Tubbs RR, Myles JL, Procop GW: HER-2 / neu
amplification in breast cancer: stratification by tumor type and
grade. Am J Clin Pathol 2002, 117:916-921 [ Özet ]
42) Moriki T, Takahashi T, Hiroi M, Yamane T, Hara H: Histological
grade in invasive ductal carcinoma of breast correlates with the
proliferative activity evaluated by BrdU: an immunohistochemical
study including correlations with p53, c-erbB-2 and estrogen
receptor status. Pathol Int 1996, 46:417-425 [ Özet ]
43) Konecny G, Pauletti G, Pegram M, Untch M, Dandekar S,
Aguilar Z, Wilson C, Rong HM, Bauerfeind I, Felber M, Wang
HJ, Beryt M, Seshadri R, Hepp H, Slamon DJ: Quantitative
association between HER-2/neu and steroid hormone receptors
in hormone receptor-positive primary breast primary breast
cancer. J Natl Cancer Inst 2003, 95:142-153 [ Özet ]
44) Fuqua SA, Fitzgerald SD, Chamness GC, Tandon AK, McDonnell
DP, Nawaz Z, O’Malley BW, McGuire WL: Variant human breast
tumor estrogen receptor with constituve transcriptional activity.
Cancer Res 1991, 51:105-109 [ Özet ]
45) Kolár Z, Murray PG, Zapletalová J: Expression of C-erb-B2
in node negative breast cancer does not correlate with estrogen
receptor status, predictors of hormone responsiveness, or PCNA
expression. Neoplasma 2002, 49:110-113 [ Özet ]
46) Smith CL: Cross-talk between peptide growth factor and estrogen
receptor signaling pathways. Biol Reprod 1998, 58:627-632 [ Özet ]
47) Bouras T, Southey MC, Venter DJ: Overexpression of the steroid
receptor coactivator AIB1 in breast cancer correlates with the
absence of estrogen and progesterone receptors and positivity for
p53 and HER-2 /neu. Cancer Res 2001, 61:903-907 [ Özet ]
48) Newman SP, Bates NP, Vernimmen D, Parker MG, Hurst HC:
Cofactor competition between the ligand-bound oestrogen
receptor end an intron 1 enhancer leads to oestrogen repression
of ERBB2 expression in breast cancer. Oncogene 2000, 19:
490-497 [ Özet ]
){kind=link}
){kind=link}
){kind=link}
){kind=link}
){kind=link}
){kind=link}
){kind=link}