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'Basal-like' breast cancer does not originate from basal stem cells
By Dross at 2010-09-03 04:36
'Basal-like' breast cancer does not originate from basal stem cells

New research uncovers a case of mistaken identity that may have a significant impact on future breast cancer prevention and treatment strategies. The study, published by Cell Press in the September 3rd issue of the journal Cell Stem Cell, suggests that despite their "stem cell-like" characteristics, most aggressive breast tumors are not derived from normal mammary gland stem cells.

The glandular tissue of the breast contains two main cell types, outer "basal" cells and inner "luminal" cells. The basal layer consists mostly of differentiated cells with a small population of mammary stem cells. The luminal layer contains differentiated cells and several types of cells which are intermediates between the luminal cells and stem cells. The different cell types can be identified and separated on the basis of specific molecular markers.

"In breast cancer, it has been proposed that different tumor subtypes may originate from different stem and intermediate cells, with more aggressive 'basal-like' breast cancers originating from basal stem cells and less aggressive breast cancers from the luminal intermediates," explains senior study author, Dr. Matthew J. Smalley from The Breakthrough Breast Cancer Research Centre at the Institute of Cancer Research in London. "Strikingly, the vast majority of breast tumors with mutations in BRCA1, a breast cancer susceptibility gene, have basal-like characteristics, suggesting a stem cell origin."

More recently, however, it was demonstrated that increases in abnormal luminal intermediate cells are associated with BRCA1 mutations and that there are similarities between the genes switched on in normal human luminal intermediate cells and basal-like breast cancer cells. "To resolve the true origin of BRCA1 breast cancer, we designed the first direct comparison of the effects of creating identical BRCA1-associated tumor predisposing events in basal stem versus luminal intermediate cells," says Dr. Smalley.

Specifically, the researchers deleted the BRCA1 gene in mouse basal stem cells or luminal intermediate cells. They discovered that although BRCA1 deletion caused tumors to form from both basal stem cells and luminal intermediate cells, only the latter had features that were identical to both human BRCA1 tumors and the majority of human basal-like breast cancers not associated with BRCA1 mutations.

Taken together, these findings suggest that the majority of so-called basal-like breast cancers are derived from luminal intermediate cells and not from basal stem cells as was originally expected. "Our results highlight luminal intermediate cells as a key to understanding the origins of basal-like breast cancer," concludes Dr. Smalley. "This has important implications for treatment and prevention strategies for this aggressive disease."


5 comments | 1757 reads

by gdpawel on Tue, 2012-10-02 07:47
Anna Azvolinsky, PhD.

Data from the Cancer Genome Atlas shows basal-like breast cancers share similar genetic origins and features with serous ovarian tumors. The large collaborative study, conducted by the National Human Genome Research Institute and the National Cancer Institute, also confirmed the previously identified four main breast cancer subtypes—luminal A, luminal B, HER2, and basal-like, each of which are molecularly distinct. The findings are published in Nature.

“This kind of comprehensive and systems approach to the problem is exactly the point of the Cancer Genome Atlas,” said Lisa A. Carey, MD, associate professor of medicine at the University of North Carolina, Chapel Hill, North Carolina.

The study is unique, analyzing a variety of different breast cancer types and using multiple technology platforms to evaluate the DNA, RNA, and protein of these tumors. The comprehensive study analyzed primary tumor samples from 825 patients using different, complementary technologies—genomic DNA copy number arrays, exome sequencing, DNA methylation, messenger RNA arrays, microRNA sequencing, and reverse-phase protein arrays. Each tumor sample was analyzed using at least one analytic tool, 463 patient tumor samples were analyzed using five of the six analytical techniques, and 348 patient samples with all six technologies.

Similarities Between Ovarian and Basal-Like Breast Cancers

In a copy number and genomic mutation analysis of all four breast cancer subtypes and ovarian cancer tumor samples, basal-like breast cancer and ovarian cancer were found be most similar. The authors highlight that the similarities between basal-like breast cancer and serous ovarian cancers indicate that these two difficult-to-treat cancer types may be able to be treated with the same therapies—chemotherapy drugs, anti-angiogenesis agents, and others in development.

Basal-like breast cancers account for approximately 10% of all breast cancers. The patient population for this subtype is younger and includes more African American than other cancer subtypes. The subtype is also associated with a higher incidence of germline BRCA1 mutations. This breast cancer type currently only has chemotherapy options. This breast cancer subtype includes triple-negative breast cancers, characterized by the aberrations they lack—HER2 overexpression, and estrogen- and progesterone(Drug information on progesterone)-receptor expression. However, about three quarters of triple-negative breast cancers are basal-like, while the other quarter had similarity to all of the other subtypes. The overall mutation spectrum of these two cancers was similar, based on previous results of ovarian cancer genome analyses. For both ovarian and basal-like breast cancer, TP53 was found mutated in 80% of tumors.

Basal-like breast cancers and ovarian cancers had similar rates of mutation and a similar spectrum of mutations. The basal-like tumors had a high frequency of mutations in the ATM, BRCA1, BRCA2, as well as RB1 loss and cyclin E1 amplification—the same mutations identified for ovarian cancers.

About 20% of basal-like breast tumors had a germline or somatic mutation in either BRCA1 or BRCA2. The authors suggest that these BRCA-mutated patients could potentially respond to Poly (ADP-ribose) polymerase (PARP) inhibitors. The analysis also showed various copy number amplifications and deletions that may be therapeutic targets.

“The central role of BRCA1 and BRCA2 in the [response to DNA damage] may have implications for chemotherapy choices or PARP inhibition,” said Dr. Carey, pointing out that both types of therapies have been pursued for both ovarian and basal-like breast cancer. “So while the genomic data are new, the therapeutic implications are being tested already.”

Breast Cancer Subtype Comparisons

Basal-like and HER2-overexpressing tumors had higher mutation rates compared to the other two subtypes. The luminal A subtype had the lowest mutation rate. These two types also had the least number of mutated genes. A fifth subtype was observed, but with only eight patient samples with this type, the authors could not provide definitive characterization of this “normal-like” breast tumor type.

Three genes—TP53, PI3KCA, and GATA3—were common to all of the four subtypes, occurring in more than 10% of the tumor samples. The spectrum of mutations identified by exome sequencing found novel and previously identified mutations. The luminal A subtype had the most “significantly mutated genes,” according to the authors, with 45% of the tumors having a PIK3CA mutation, followed by high frequencies of mutations in MAP3K1, GATA3, TP53, CDH1, and MAP2K4. Luminal B breast cancers had a 29% frequency of TP53 and PIK3CA mutations—the most frequently mutated genes in this breast cancer type. Basal-like cancers had a TP53 mutation in 80% of the tumors sample, and 9% had a PIK3CA mutation. These were the only two gene mutations found in common between the basal-like and luminal subtypes. HER2 was amplified in 80% of HER2-breast cancers. TP53 mutations were found in 72% of these cancers, and 39% had a PI3KCA mutation. In general mutations in TP53 have been linked to a poorer outcome for patients.

Analyzing the DNA of normal tissue samples, approximately 10% of the patients were found to harbor a germline mutation in nine different genes that may confer a predisposition to breast cancer, including BRCA1, BRCA2, PTEN, and RAD51C, among others. This suggests that some sporadic breast cancer patients actually may have a genetic component.

How feasible are these massive whole-genome and proteome tumor analyses? “They are less massive now than they used to be, and it is likely that this sort of comprehensive evaluation will be key to understanding individual tumor biology,” said Carey. To make this analysis really comprehensive, according to Carey, the tumor microenvironment should also be assessed, as it is likely to have effects on the evolution of a cancer.

Kevin Kalinsky, M.D.

The phosphoinositide-3 kinase (PI3K) pathway is an important target in breast cancer research. The PI3K pathway is critical for a number of functions at the cancer cellular level, including proliferation and survival. Abnormalities activating the PI3K pathway, such as mutations, are common in breast cancer. The majority of these mutations occur in the PIK3CA gene, which encodes the human PI3K p110α protein. These mutations can enhance downstream PI3K pathway signaling elements, such as cellular growth and survival, and promote oncogenic transformation. PIK3CA mutations occur in approximately 1/3rd of breast cancers.

The results from the Cancer Genome Atlas Network reported in 2012 confirm that PIK3CA mutations are particularly frequent in certain types of breast cancers, such as hormone receptor positive breast tumors. Within hormone receptor positive breast cancers, PIK3CA mutations are more common in luminal A tumors (PIK3CA mutation rate: 49%), which are more slowly proliferative tumors than luminal B tumors (PIK3CA mutation rate: 32%). PIK3CA mutations occur with a frequency of 42% in the HER2 subtype. In early-stage breast cancer, there is consistent data demonstrating that the presence of PIK3CA mutations associate with an improved prognosis. Given the frequency of abnormalities in the PI3K pathway, there are a number of agents in various stages of clinical development that are targeting the pathway.

Affinitor (Everolimus) is a FDA-approved drug that inhibits mTOR, which is downstream of PI3K. The current FDA indication is in combination with the aromatase inhibitor exemestane for postmenopausal women with hormone-receptor positive, HER2 negative metastatic breast cancer who have previously been treated with letrozole or anastrazole. There is ongoing research to determine whether the presence or absence of PIK3CA mutations can predict benefit to these PI3K pathway-targeted drugs and whether this predictive behavior is different role in hormone receptor positive tumors as compared to HER2 positive tumors.

Note: According to laboratory oncologist Dr. Robert A. Nagourney, the PI3K pathway is an area of rapidly growing interest as new compounds target this key regulatory protein complex. Both selective and non-selective (pan PI3K) inhibitors are in clinical testing. Paul Workman's group was honored for their seminal work in this and related areas of drug development. Dr. Nagourney has reported his findings on the dual PI3K/mTOR inhibitor BEZ235 (Nagourney, RA et al, Proc AACR, 2586, 2012).

Reports from the San Antonio breast symposium held in Texas last December, provide two new findings.

The first is a clinical trial testing the efficacy of pertuzumab. This novel monoclonal antibody functions by preventing dimerization of HER-2 (The target of Herceptin) with the other members of the human epidermal growth factor family HER-1, HER-3 and HER-4. In so doing, the cross talk between receptors is abrogated and downstream signaling in squelched.

The second important finding regards the use of everolimus. This small molecule derivative of rapamycin blocks cellular signaling through the mTOR pathway. Combining everolimus with the aromatase inhibitor exemestane, improved time to progression.

While these two classes of drugs are different, the most interesting aspect of both reports reflects the downstream pathways that they target. Pertuzumab inhibits signaling at the PI3K pathway, upstream from mTOR. Everolimus blocks mTOR itself, thus both drugs are influencing cell signaling that channel through metabolic pathways PI3K is the membrane signal from insulin, while mTOR is an intermediate in the same pathway. Thus, these are in truest sense of the word, breakthroughs in metabolomics.

Protein Kinase Inhibitors in Cancer Treatment: Mixing and Matching?


by gdpawel on Thu, 2012-10-04 07:09
(MedPage Today) - Analysis of gene-expression profiles has led to identification of four distinct breast cancer subtypes, each of which has numerous subtype-specific and novel mutations, data from an NCI-sponsored research program showed.

The profiles subdivided breast cancer into luminal A, luminal B, HER2, and basal-like subtypes. The analysis identified almost all genes previously implicated in breast cancer but also revealed a number of novel genes not previously recognized as playing a role in breast cancer etiology.

The findings provide a basis for moving forward with research into the origin and treatment of breast cancer, according to a report published online in Nature.

More importantly, the findings may effect fundamental changes in the way breast cancer is defined, studied, and treated, Charles Perou, PhD, of the University of North Carolina in Chapel Hill, told MedPage Today.

"These are terms that we believe are based on the molecular features and genetic wiring of these tumors as opposed to how they look, although, of course, there are also correlations with how they look," said Perou.

"But now we are bringing it to the molecular and cellular level and providing much more detailed explanations as for why there is a cancer and how this differs across the different breast cancer patients."

Clinically, breast cancer has fallen into three broad categories on the basis of therapeutic approaches: Estrogen-receptor (ER) positive, HER2 amplified, and basal-like (commonly called triple-negative breast cancer).

Advances in genetics and molecular biology have fueled growth in techniques and capabilities for analyzing breast cancer genetics, which will offer more insight into the origin of breast cancer, as well as clues to developing more effective therapy.

Perou and other participants in the Cancer Genome Atlas Network helped set the stage for future research by analyzing tumor and germline DNA samples from 825 patients with breast cancer.

Samples from different subgroups of patients were analyzed by means of six different assay platforms: mRNA expression microarrays, DNA methylation, single nucleotide polymorphism arrays, microRNA sequencing, whole-exome sequencing, and reverse-phase protein array.

Whole-exome sequencing of 510 tumors from 507 patients revealed 30,626 somatic mutations, consisting of 28,319 point mutations, four dinucleotide mutations, and 2,302 insertion/deletions. Of 19,045 missense mutations, 9,484 had a high probability of being harmful.

Subsequent analyses showed that significantly mutated genes occur more frequently and with greater diversity in luminal A and luminal B tumors as compared with basal-like and HER2-enriched breast cancers. However, the luminal A subtype had the lowest overall mutation rate, whereas basal-like and HER2-enriched tumors had the highest rates.

Each tumor subtype exhibited mutation types and frequencies that were more common or specific to the subtype, whereas some mutations occurred in more than one subtype.

Basal-like tumors had the most distinctive profiles and differed substantially from luminal and HER2-enriched tumors. Basal-like tumors shared a number of characteristics common to ovarian cancer, suggesting a common etiologic pathway and possibly similar susceptibility to some of the same therapies.

"The integrated molecular analyses of breast carcinomas that we report here significantly extends our knowledge base to produce a comprehensive catalogue of likely genomic drivers of the most common breast cancer subtypes," Perou and coauthors wrote in conclusion.

"Our novel observation that diverse genetic and epigenetic alterations converge phenotypically into four main breast cancer classes is not only consistent with convergent evolution of gene circuits, as seen across multiple organisms, but also with models of breast cancer clonal expansion and in vivo cell selection proposed to explain the phenotypic heterogeneity observed within defined breast cancer subtypes."

The analyses suggested numerous potential targets for existing and development drugs, as well as new types of drugs that warrant consideration for future development.

The initial report was based on data from the Cancer Genome Atlas and the findings primarily provide a baseline or reference for future work, said another participant in the research network and coauthor of the report.

"What is exciting about this report is that basic scientists working in breast cancer need to know about the types and frequencies of mutations associated with breast cancer, and these data provide that information," Ana Maria Gonzalez-Angulo, MD, of the University of Texas MD Anderson Cancer Center in Houston, told MedPage Today. "Researchers will have access to all of it.

"Another key point about the report is the finding that different (genetic) players are important in different breast cancer subtypes. Fortunately, for most of those players, today we have drugs available that are in clinical trials and are being studied in the appropriate way."

The work was supported by the National Cancer Institute, Susan G. Komen for the Cure, the US Department of Defense, and the Breast Cancer Research Foundation.


Department of Defense Breast Cancer Research Program, May 2013 The Breast Cancer Landscape


Somatic Mutation Profiling and Associations With Prognosis and Trastuzumab Benefit in Early Breast Cancer


Note: Targeted "genotyping" cannot show any statistically significant associations with trastuzumab benefit.

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