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Loss of the retinoblastoma tumor suppressor is a common event in Basal-like and Luminal B breast carcinomas

ABSTRACT: Breast cancers can be classified using whole genome expression into distinct subtypes that show differences in patient prognosis. One of these groups, the basal-like carcinomas, are poorly differentiated, highly metastatic, and genomically unstable. These tumors also contain specific genetic alterations with one example being frequent p53 mutations. The loss of the tumor suppressor gene encoded by the retinoblastoma (RB1) locus is a well-characterized occurrence in many tumor types, however, its role in breast cancer is less clear with many reports demonstrating a Loss of Heterozygosity (LOH) that does not correlate with loss of RB1 protein expression. Here we report that LOH of the RB1 locus was observed at a high frequency in basal-like and luminal B tumors. These tumors also concurrently have low expression of RB1 mRNA as assessed by DNA microarray. As in previous reports, we also did not see a significant correlation between RB1 LOH and protein expression as measured by immunohistochemistry (IHC). p16INK4a, however, was highly expressed both by microarray and IHC, in basal-like tumors only presumably due to a previously reported feedback loop caused by RB1 loss. These results suggest that the functional loss of RB1 is a common event in the progression of basal-like and luminal B breast tumors, which may play a key role in dictating therapeutic responses Keywords: reference x sample Comparison of reference samples against treatment

ORGANISM(S): Homo sapiens

SUBMITTER: Herschkowitz JI

PROVIDER: S-ECPF-GEOD-10884 | biostudies-other | 2008

REPOSITORIES: biostudies-other

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Loss of the retinoblastoma tumor suppressor is a common event in Basal-like and Luminal B breast carcinomas

Project description:Breast cancers can be classified using whole genome expression into distinct subtypes that show differences in patient prognosis. One of these groups, the basal-like carcinomas, are poorly differentiated, highly metastatic, and genomically unstable. These tumors also contain specific genetic alterations with one example being frequent p53 mutations. The loss of the tumor suppressor gene encoded by the retinoblastoma (RB1) locus is a well-characterized occurrence in many tumor types, however, its role in breast cancer is less clear with many reports demonstrating a Loss of Heterozygosity (LOH) that does not correlate with loss of RB1 protein expression. Here we report that LOH of the RB1 locus was observed at a high frequency in basal-like and luminal B tumors. These tumors also concurrently have low expression of RB1 mRNA as assessed by DNA microarray. As in previous reports, we also did not see a significant correlation between RB1 LOH and protein expression as measured by immunohistochemistry (IHC). p16INK4a, however, was highly expressed both by microarray and IHC, in basal-like tumors only presumably due to a previously reported feedback loop caused by RB1 loss. These results suggest that the functional loss of RB1 is a common event in the progression of basal-like and luminal B breast tumors, which may play a key role in dictating therapeutic responses Keywords: reference x sample Comparison of reference samples against treatment

2010-06-25 | E-GEOD-10884 | biostudies-arrayexpress

The functional loss of the retinoblastoma tumour suppressor is a common event in basal-like and luminal B breast carcinomas.

Project description:Breast cancers can be classified using whole genome expression into distinct subtypes that show differences in prognosis. One of these groups, the basal-like subtype, is poorly differentiated, highly metastatic, genomically unstable, and contains specific genetic alterations such as the loss of tumour protein 53 (TP53). The loss of the retinoblastoma tumour suppressor encoded by the RB1 locus is a well-characterised occurrence in many tumour types; however, its role in breast cancer is less clear with many reports demonstrating a loss of heterozygosity that does not correlate with a loss of RB1 protein expression.We used gene expression analysis for tumour subtyping and polymorphic markers located at the RB1 locus to assess the frequency of loss of heterozygosity in 88 primary human breast carcinomas and their normal tissue genomic DNA samples.RB1 loss of heterozygosity was observed at an overall frequency of 39%, with a high frequency in basal-like (72%) and luminal B (62%) tumours. These tumours also concurrently showed low expression of RB1 mRNA. p16INK4a was highly expressed in basal-like tumours, presumably due to a previously reported feedback loop caused by RB1 loss. An RB1 loss of heterozygosity signature was developed and shown to be highly prognostic, and was potentially a predictive marker of response to neoadjuvant chemotherapy.These results suggest that the functional loss of RB1 is common in basal-like tumours, which may play a key role in dictating their aggressive biology and unique therapeutic responses.

| S-EPMC2614508 | biostudies-literature

Loss of the retinoblastoma tumor suppressor is a common event in Basal-like and Luminal B breast carcinomas

2008-09-18 | GSE10884 | GEO

The retinoblastoma tumor suppressor modifies the therapeutic response of breast cancer.

Project description:The retinoblastoma tumor suppressor (RB) protein is functionally inactivated in the majority of human cancers and is aberrant in one-third of all breast cancers. RB regulates G(1)/S-phase cell-cycle progression and is a critical mediator of antiproliferative signaling. Here the specific impact of RB deficiency on E2F-regulated gene expression, tumorigenic proliferation, and the response to 2 distinct lines of therapy was investigated in breast cancer cells. RB knockdown resulted in RB/E2F target gene deregulation and accelerated tumorigenic proliferation, thereby demonstrating that even in the context of a complex tumor cell genome, RB status exerts significant control over proliferation. Furthermore, the RB deficiency compromised the short-term cell-cycle inhibition following cisplatin, ionizing radiation, and antiestrogen therapy. In the context of DNA-damaging agents, this bypass resulted in increased sensitivity to these agents in cell culture and xenograft models. In contrast, the bypass of antiestrogen signaling resulted in continued proliferation and xenograft tumor growth in the presence of tamoxifen. These effects of aberrations in RB function were recapitulated by ectopic E2F expression, indicating that control of downstream target genes was an important determinant of the observed responses. Specific analyses of an RB gene expression signature in 60 human patients indicated that deregulation of this pathway was associated with early recurrence following tamoxifen monotherapy. Thus, because the RB pathway is a critical determinant of tumorigenic proliferation and differential therapeutic response, it may represent a critical basis for directing therapy in the treatment of breast cancer.

| S-EPMC1679964 | biostudies-literature

ZNF703 is a common Luminal B breast cancer oncogene that differentially regulates luminal and basal progenitors in human mammary epithelium.

Project description:The telomeric amplicon at 8p12 is common in oestrogen receptor-positive (ER+) breast cancers. Array-CGH and expression analyses of 1172 primary breast tumours revealed that ZNF703 was the single gene within the minimal amplicon and was amplified predominantly in the Luminal B subtype. Amplification was shown to correlate with increased gene and protein expression and was associated with a distinct expression signature and poor clinical outcome. ZNF703 transformed NIH 3T3 fibroblasts, behaving as a classical oncogene, and regulated proliferation in human luminal breast cancer cell lines and immortalized human mammary epithelial cells. Manipulation of ZNF703 expression in the luminal MCF7 cell line modified the effects of TGF? on proliferation. Overexpression of ZNF703 in normal human breast epithelial cells enhanced the frequency of in vitro colony-forming cells from luminal progenitors. Taken together, these data strongly point to ZNF703 as a novel oncogene in Luminal B breast cancer.

| S-EPMC3395113 | biostudies-literature

The retinoblastoma tumor suppressor pathway modulates the invasiveness of ErbB2-positive breast cancer.

Project description:The processes that control the progression of ductal carcinoma in situ (DCIS) to invasive breast cancer remain poorly understood. Epidermal growth factor receptor 2 (ErbB2) overexpression is common in DCIS, as is disruption of the retinoblastoma tumor suppressor (RB) pathway. Here, we examined the cooperative impact of ErbB2 and RB deregulation on facets of disease progression. Our studies demonstrate that RB deficiency altered the expression of key molecules needed for proper cellular organization and epithelial cell-cell adhesion as part of a program related to the epithelial-to-mesenchymal transition (EMT). An increase in the invasive potential of ErbB2-overexpressing cells was observed upon RB depletion. Further, stable knockdown of RB resulted in invasive lesions in orthotopic xenograft assays, compared with DCIS-like lesions developing from RB-proficient cells. Conversely, the invasive phenotype observed in ErbB2-positive cancer models was inhibited through CDK4/6 inhibition in an RB-dependent manner. Finally, in a cohort of DCIS cases, we show that, although elevated levels of ErbB2 are associated with increased risk of a subsequent DCIS recurrence, it is not associated with progression to invasive disease. In contrast, RB loss in ErbB2-positive DCIS cases was associated with increased risk for invasive breast cancer. Taken together, these data demonstrate a key role for the RB pathway in invasion associated with breast tumor progression, and shed light on the key molecular events that promote the progression of DCIS to invasive disease.

| S-EPMC4150690 | biostudies-literature

Retinoblastoma tumor suppressor pathway in breast cancer: prognosis, precision medicine, and therapeutic interventions.

Project description:A series of recent studies have demonstrated that the retinoblastoma tumor suppressor (RB) pathway plays a critical role in multiple clinically relevant aspects of breast cancer biology, spanning early stage lesions to targeted treatment of metastatic disease. In ductal carcinoma in situ, multiple groups have shown that dysregulation of the RB pathway is critically associated with recurrence and disease progression. Functional models have similarly illustrated key roles for RB in regulating epithelial-mesenchymal transition and other features contributing to aggressive disease. Invasive breast cancers are treated in distinct fashions, and heterogeneity within the RB pathway relates to prognosis and response to commonly used therapeutics. Luminal B breast cancers that have a poor prognosis amongst estrogen receptor-positive disease are defined based on the expression of RB-regulated genes. Such findings have led to clinical interventions that directly target the RB pathway through CDK4/6 inhibition which have promise in both estrogen receptor-positive and Her2-positive disease. In contrast, RB loss results in improved response to chemotherapy in triple-negative breast cancer, where ongoing research is attempting to define intrinsic vulnerabilities for targeted intervention. These findings support a wide-reaching impact of the RB pathway on disease that could be harnessed for improved clinical interventions.

| S-EPMC4076637 | biostudies-literature

Potential tumor suppressor role for the c-Myb oncogene in luminal breast cancer.

Project description:The transcription factor c-Myb has been well characterized as an oncogene in several human tumor types, and its expression in the hematopoietic stem/progenitor cell population is essential for proper hematopoiesis. However, the role of c-Myb in mammopoeisis and breast tumorigenesis is poorly understood, despite its high expression in the majority of breast cancer cases (60-80%).We find that c-Myb high expression in human breast tumors correlates with the luminal/ER+ phenotype and a good prognosis. Stable RNAi knock-down of endogenous c-Myb in the MCF7 luminal breast tumor cell line increased tumorigenesis both in vitro and in vivo, suggesting a possible tumor suppressor role in luminal breast cancer. We created a mammary-derived c-Myb expression signature, comprised of both direct and indirect c-Myb target genes, and found it to be highly correlated with a published mature luminal mammary cell signature and least correlated with a mammary stem/progenitor lineage gene signature.These data describe, for the first time, a possible tumor suppressor role for the c-Myb proto-oncogene in breast cancer that has implications for the understanding of luminal tumorigenesis and for guiding treatment.

| S-EPMC2951337 | biostudies-literature

Tumor Suppressor Role for the c-Myb Oncogene in Luminal Breast Cancer

Project description:The transcription factor c-Myb has been well characterized as an oncogene in several human tumor types, and its expression in the hematopoietic stem/progenitor cell population is essential for proper hematopoiesis. However, the role of c-Myb in mammopoeisis and breast tumorigenesis is poorly understood, despite its high expression in the majority of breast cancer cases (60-80%). We find that c-Myb high expression in human breast tumors correlates with the luminal/ER+ phenotype and a good prognosis. RNAi knock-down of endogenous c-Myb levels in the MCF7 luminal breast tumor cell line increases tumorigenesis both in vitro and in vivo, suggesting a tumor suppressor role in luminal breast cancer. We created a mammary-derived c-Myb expression signature and found it to be highly correlated with a published mature luminal mammary cell signature and least correlated with a mammary stem/progenitor lineage gene signature. These data describe, for the first time, a tumor suppressor role for the c-Myb proto-oncogene in breast cancer that has implications for understanding luminal tumorigenesis and for guiding treatment. refXsample

| S-ECPF-GEOD-21371 | biostudies-other

Transcriptome analysis of basal and luminal tumor-initiating cells in ErbB2-driven breast cancer.

Project description:Breast cancer is the leading cause of cancer-related mortality for females worldwide.1 Improving early screening strategies and understanding the events that lead to tumor initiation have led to demonstrable improvements in clinical outcome. Our previous work revealed a variance in the tumorigenic capacity between different mammary epithelial cell populations in an MMTV-ErbB2 mouse model. In order to greater understand how different mammary epithelial cells influence the tumorigenic capacity in ErbB2-induced breast cancer, we transplanted different cell populations from pre-neoplastic MMTV-ErbB2 female mice into recipient mice for tumorigenic study. We found that different mammary epithelial cells bear different tumorigenic potential even when induced by the same ErbB2 proto-oncogene. To understand the difference in tumors formed from different epithelial cells, we performed gene expression profiling using these tumors (GSE64487). Several genes were further validated using real-time reverse transcription polymerase chain reaction (RT-PCR). Here we provide further details on the experimental methods and microarray analysis. This data provides a resource to further understanding how different mammary cell populations can initiate ErbB2-driven tumors and the role of these cell populations as putative tumor-initiating cells (TICs).

| S-EPMC4493742 | biostudies-literature

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