Dataset Information

Molecular apocrine breast cancers are aggressive estrogen receptor negative tumors overexpressing either HER2 or GCDFP15.

ABSTRACT:

Introduction

Molecular apocrine (MA) tumors are estrogen receptor (ER) negative breast cancers characterized by androgen receptor (AR) expression. We analyzed a group of 58 transcriptionally defined MA tumors and proposed a new tool to identify these tumors.

Methods

We performed quantitative reverse transcription PCR (qRT-PCR) for ESR1, AR, FOXA1 and AR-related genes, and immunohistochemistry (IHC) for ER, PR, Human Epidermal Growth Factor Receptor 2 (HER2), CK5/6, CK17, EGFR, Ki67, AR, FOXA1 and GCDFP15 and we analyzed clinical features.

Results

MA tumors were all characterized by ESR1(-) AR(+) FOXA1(+) and AR-related genes positive mRNA profile. IHC staining on these tumors showed 93% ER(-), only 58% AR(+) and 90% FOXA1(+). 67% and 57% MA tumors were HER2(3+) and GCDFP15(+), respectively. Almost all MA tumors (94%) had the IHC signature HER2(3+) or GCDFP15(+) but none of the 13 control basal-like (BL) tumors did. Clinically, MA tumors were rather aggressive, with poor prognostic factors.

Conclusion

MA tumors could be better defined by their qRT-PCR-AR profile than by AR IHC. In addition, we found that HER2 or GCDFP15 protein overexpression is a sensitive and specific tool to differentiate MA from BL in the context of ER negative tumors. A composite molecular and IHC signature could, therefore, help to identify MA tumors in daily practice.

SUBMITTER: Lehmann-Che J

PROVIDER: S-EPMC4053236 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Publications

Molecular apocrine breast cancers are aggressive estrogen receptor negative tumors overexpressing either HER2 or GCDFP15.

Lehmann-Che Jacqueline J Hamy Anne-Sophie AS Porcher Raphaël R Barritault Marc M Bouhidel Fatiha F Habuellelah Hanadi H Leman-Detours Solenne S de Roquancourt Anne A Cahen-Doidy Laurence L Bourstyn Edwige E de Cremoux Patricia P de Bazelaire Cedric C Albiter Marcela M Giacchetti Sylvie S Cuvier Caroline C Janin Anne A Espié Marc M de Thé Hugues H Bertheau Philippe P

Breast cancer research : BCR 20130511 3

<h4>Introduction</h4>Molecular apocrine (MA) tumors are estrogen receptor (ER) negative breast cancers characterized by androgen receptor (AR) expression. We analyzed a group of 58 transcriptionally defined MA tumors and proposed a new tool to identify these tumors.<h4>Methods</h4>We performed quantitative reverse transcription PCR (qRT-PCR) for ESR1, AR, FOXA1 and AR-related genes, and immunohistochemistry (IHC) for ER, PR, Human Epidermal Growth Factor Receptor 2 (HER2), CK5/6, CK17, EGFR, Ki6 ...[more]

PMID: 23663520

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Project description:BackgroundBreast cancers with 1-10% cell staining for estrogen receptor (ER) present particular clinical features. The clinical data of estrogen receptor expression level and treatment effect are limited, particularly regarding chemotherapy benefit. We evaluated the pathologic response to neoadjuvant chemotherapy (NAC) in ER low positive tumors (ER staining 1-10%) and compared it with ER > 10% positive tumors (ER staining > 10%) and ER-negative tumors. We further explored the differences in recurrence and survival with respect to the ER expression level.MethodPatients with stages II and III HER2-negative primary breast cancer who received neoadjuvant chemotherapy followed by definitive surgery were categorized according to their ER percentages into three groups: ER-negative, ER low positive, and ER > 10% positive. Logistic regression models were used to assess the association between each variable and pathologic complete response (pCR). Kaplan‒Meier analysis was used to estimate survival outcomes. Cox models were used to adjust for patient and tumor characteristics.ResultsA total of 241 patients were analyzed. Of all patients included, 22 (9.1%) had ER low positive tumors, 159 (66.0%) had ER > 10% positive tumors, and 60 (24.9%) were ER-negative. Low ER positivity was significantly associated with a higher pCR rate than ER > 10% positivity (OR, 0.249; 95% CI, 0.067-0.923; P = 0.038). After a median follow-up time of 32 months, the disease-free survival (DFS) and overall survival (OS) of the patients with ER low positive tumors were significantly worse than those of the patients with ER > 10% positive tumors but similar to those with ER-negative tumors. After adjustment for covariates, ER low positive tumors were significantly associated with worse DFS than ER > 10% positive tumors.ConclusionOur results indicated that ER low positive breast cancer presents a better response to neoadjuvant chemotherapy and significantly worse prognosis for patients than those with ER > 10% positive tumors, but similar to the ER-negative group. These data support that this category of patients behaves clinically like patients with ER-negative breast cancer and should be treated differently from patients with ER > 10% positive tumors. Further prospective study is needed.

Project description:The clinical significance of progesterone receptor (PgR) expression in estrogen receptor-negative (ER-) breast cancer is controversial. Herein, we systemically investigate the clinicopathologic features, molecular essence, and endocrine responsiveness of ER-/PgR+/HER2- phenotype.Four study cohorts were included. The first and second cohorts were from the Surveillance, Epidemiology, and End Results database (n?=?67,932) and Fudan University Shanghai Cancer Center (n?=?2,338), respectively, for clinicopathologic and survival analysis. The third and fourth cohorts were from two independent publicly available microarray datasets including 837 operable cases and 483 cases undergoing neoadjuvant chemotherapy, respectively, for clinicopathologic and gene-expression analysis. Characterized genes defining subgroups within the ER-/PgR+/HER2- phenotype were determined and further validated.Clinicopathologic features and survival outcomes of the ER-/PgR+ phenotype fell in between the ER+/PgR+ and ER-/PgR- phenotypes, but were more similar to ER-/PgR-. Among the ER-/PgR+ phenotype, 30% (95% confidence interval [CI] 17-42%, pooled by a fixed-effects method) were luminal-like and 59% (95% CI 45-72%, pooled by a fixed-effects method) were basal-like. We further refined the characterized genes for subtypes within the ER-/PgR+ phenotype and developed an immunohistochemistry-based method that could determine the molecular essence of ER-/PgR+ using three markers, TFF1, CK5, and EGFR. Either PAM50-defined or immunohistochemistry-defined basal-like ER-/PgR+ cases have a lower endocrine therapy sensitivity score compared with luminal-like ER-/PgR+ cases (P <0.0001 by Mann-Whitney test for each study set and P <0.0001 for pooled standardized mean difference in meta-analysis). Immunohistochemistry-defined basal-like ER-/PgR+ cases might not benefit from adjuvant endocrine therapy (log-rank P?=?0.61 for sufficient versus insufficient endocrine therapy).The majority of ER-/PgR+/HER2- phenotype breast cancers are basal-like and associated with a lower endocrine therapy sensitivity score. Additional studies are needed to validate these findings.

Project description:BackgroundDirectly comparing gene expression profiles of estrogen receptor-positive (ER+) and estrogen receptor-negative (ER-) breast cancers cannot determine whether differentially expressed genes between these two subtypes result from dysregulated expression in ER+ cancer or ER- cancer versus normal controls, and thus would miss critical information for elucidating the transcriptomic difference between the two subtypes.Principal findingsUsing microarray datasets from TCGA, we classified the genes dysregulated in both ER+ and ER- cancers versus normal controls into two classes: (i) genes dysregulated in the same direction but to a different extent, and (ii) genes dysregulated to opposite directions, and then validated the two classes in RNA-sequencing datasets of independent cohorts. We showed that the genes dysregulated to a larger extent in ER+ cancers than in ER- cancers enriched in glycerophospholipid and polysaccharide metabolic processes, while the genes dysregulated to a larger extent in ER- cancers than in ER+ cancers enriched in cell proliferation. Phosphorylase kinase and enzymes of glycosylphosphatidylinositol (GPI) anchor biosynthesis were upregulated to a larger extent in ER+ cancers than in ER- cancers, whereas glycogen synthase and phospholipase A2 were downregulated to a larger extent in ER+ cancers than in ER- cancers. We also found that the genes oppositely dysregulated in the two subtypes significantly enriched with known cancer genes and tended to closely collaborate with the cancer genes. Furthermore, we showed the possibility that these oppositely dysregulated genes could contribute to carcinogenesis of ER+ and ER- cancers through rewiring different subpathways.ConclusionsGPI-anchor biosynthesis and glycogenolysis were elevated and hydrolysis of phospholipids was depleted to a larger extent in ER+ cancers than in ER- cancers. Our findings indicate that the genes oppositely dysregulated in the two subtypes are potential cancer genes which could contribute to carcinogenesis of both ER+ and ER- cancers through rewiring different subpathways.

Dataset Information

Molecular apocrine breast cancers are aggressive estrogen receptor negative tumors overexpressing either HER2 or GCDFP15.

Introduction

Methods

Results

Conclusion

Publications

Molecular apocrine breast cancers are aggressive estrogen receptor negative tumors overexpressing either HER2 or GCDFP15.

Similar Datasets

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