Malevolent Desiger News - How Breast Cancer is 'Designed'

Malevolent Designer News

How Breast Cancer is 'Designed'

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How Breast Cancer Arises | Harvard Medical School

Bear in mind that Creationists believe all parts of the human body, indeed all parts of every living organism, were intelligently designed by an omniscience and omnipotent god. With omniscience comes inerrant foresight of the consequences of any particular design, so, whatever the design does, must be the intended outcome of the design, or else the designer is not omniscient and needs to wait to find out what its design does.

In that case it can't be described as omniscience, but still being intelligent, it should be capable of discarding a design that doesn't do what it wants and starting again. In other words, it should be capable of ensuring that anything it designs does exactly what it wanted it to do, and should do it efficiently, with minimal waste and with the minimal complexity.

In other words, omniscient or not, its designs should comply with the basic principles of intelligent design - minimal waste, minimal complexity and maximal fitness for a clear purpose and endurance over time.

Sadly, for creationists that's not what we see; instead, we see evidence of utilitarianism. Whatever conveys a short-term benefit in terms of producing more offspring that go on to reproduce, is retained, regardless of any long-term detriment, provided the short-term benefits outweigh the long-term detriments. However, the result is often suboptimal compared to what it would have been had there been no detrimental effects, or had the design been more efficient at what it does.

One of the pieces of evidence for utilitarian design is the replication of the entire genome in every cell in multicellular species, when only a small portion of it is needed in specialised cells, and a characteristic of multicellularity is cell specialisations. This ludicrously wasteful method of cell reproduction, retained because it was the method used in the ancestral single-celled species, has meant that a complex system of epigenetics is needed to turn off the unwanted genes and to ensure just the right genes are active when needed. It also requires another complex mechanism for detecting and repairing the frequent mistakes that replicating billions of base pairs of DNA inevitably produce, because the method of replication is far from perfectly designed.

For more about epigenetics and why it is needed, see The Unintelligent Designer: Refuting the Intelligent Design Hoax, pp. 109-115

The result is two of the hallmarks of bad design - prolific waste and unnecessary complexity. And now, as shown by this piece of research by Harvard Medical School scientists, harmful consequences. As though the risks of developing a cancer due to run-away replication of cells, as sometimes happens when cell replication goes wrong, the scientists have discovered that one of the types of one of the commonest cancers, breast cancer, is caused when the sex hormone, oestragen, needed for reproduction, enhances the probability of things going wrong and producing a cancer.

Traditionally, creationists faced with this sort of evidence against intelligent design, resort to religious mumbo-jumbo and start gibbering about 'The Fall' allowing 'sin' to enter the world, as though there is some other intelligence, empowered by 'sin' against which their supposedly omnipotent god is powerless, or this thing called 'sin' is itself capable of intelligently creating things. But what of these problems - the result of cell replication going wrong because of the sex hormone that in needed for reproduction in women, did their putative designer not design? Cell reproduction or sexual reproduction?

The research and its significance are explained in a Harvard Medical School press release by Ekaterina Pesheva:

At a glance:

• Researchers trace the origin of certain breast cancers to genomic reshuffling — rearrangement of chromosomes — that activates cancer genes and ignites disease.
• The finding offers a long-missing explanation for many cases of the disease that remain unexplained by the classical model of breast cancer development.
• The study shows the sex hormone estrogen — thus far thought to be only a fuel for breast cancer growth — can directly cause tumor-driving genomic rearrangements.

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In what may turn out to be a long-missing piece in the puzzle of breast cancer, Harvard Medical School researchers have identified the molecular sparkplug that ignites cases of the disease currently unexplained by the classical model of breast-cancer development.

A report on the team’s work is published May 17 in Nature.

We have identified what we believe is the original molecular trigger that initiates a cascade culminating in breast tumor development in a subset of breast cancers that are driven by estrogen.

Professor Peter Park, senior investigator
Professor of Biomedical Informatics
Blavatnik Institute
Harvard Medical School, Boston, MA, USA

The researchers said as many as one-third of breast cancer cases may arise through the newly identified mechanism.

The study also shows that the sex hormone estrogen is the culprit behind this molecular dysfunction because it directly alters a cell’s DNA.

Most, though not all, breast cancers are fueled by hormonal fluctuations. The prevailing view of estrogen’s role in breast cancer is that it acts as a catalyst for cancer growth because it stimulates the division and proliferation of breast tissue, a process that carries the risk for cancer-causing mutations. The new work, however, shows that estrogen causes mischief in a far more direct manner.

Our work demonstrates that estrogen can directly induce genomic rearrangements that lead to cancer, so its role in breast cancer development is both that of a catalyst and a cause.

Jake June-Koo Lee, first author
Former research fellow, Harvard Medical School
Now Department of Medicine
Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Although the work has no immediate implications for therapy, it could inform the design of tests that can track treatment response and could help doctors detect the return of tumors in patients with a history of certain breast cancers.

Birth of a cancer cell

The human body is made up of hundreds of trillions of cells. Most of these cells are constantly dividing and replicating, a process that sustains the function of organs day after day, over a lifetime.

With each division, a cell makes a copy of its chromosomes — bundles of tightly compressed DNA — into a new cell. But this process sometimes goes awry, and DNA can break. In most cases, these DNA breaks get swiftly mended by the molecular machinery that guards the integrity of the genome. However, every now and then, the repair of broken DNA gets botched, causing chromosomes to get misplaced or scrambled inside a cell.

Many human cancers arise in this manner during cell division, when chromosomes get rearranged and awaken dormant cancer genes that can trigger tumor growth.

One such chromosomal scramble can occur when a chromosome breaks, and a second copy of the broken chromosome is made before the break gets fixed.

Then, in what ends up being a botched repair attempt, the broken end of one chromosome is fused to the broken end of its sister copy rather than to its original partner. The resulting new structure is a misshapen, malfunctioning chromosome.

During the next cell division, the misshapen chromosome is stretched between the two emerging daughter cells and the chromosome “bridge” breaks, leaving behind shattered fragments that contain cancer genes to multiply and get activated.

Certain human cancers, including some breast cancers, arise when a cell’s chromosomes get rearranged in this way. This malfunction was first described in the 1930s by Barbara McClintock, who went on to win the Nobel Prize in Physiology or Medicine in 1983.

Cancer experts can often identify this particular aberration in tumor samples by using genomic sequencing. Yet, a portion of breast cancer cases do not harbor this mutational pattern, raising the question: What is causing these tumors?

These were the “cold” cases that intrigued study authors Park and Lee. Looking for answers, they analyzed the genomes of 780 breast cancers obtained from patients diagnosed with the disease. They expected to find the classical chromosomal disarray in most of the tumor samples, but many of the tumor cells bore no trace of this classic molecular pattern.

Instead of the classic misshapen and improperly patched-up single chromosome, they saw that two chromosomes had fused, suspiciously near “hot spots” where cancer genes are located.

Just as in McClintock’s model, these rearranged chromosomes had formed bridges, except in this case, the bridge contained two different chromosomes. This distinctive pattern was present in one-third (244) of the tumors in their analysis.

Lee and Park realized they had stumbled upon a new mechanism by which a “disfigured” chromosome is generated and then fractured to fuel the mysterious breast cancer cases.

A new role for estrogen in breast cancer?

When the researchers zoomed onto the hot spots of cancer-gene activation, they noticed that these areas were curiously close to estrogen-binding areas on the DNA.

Estrogen receptors are known to bind to certain regions of the genome when a cell is stimulated by estrogen. The researchers found that these estrogen-binding sites were frequently next to the zones where the early DNA breaks took place.

This offered a strong clue that estrogen might be somehow involved in the genomic reshuffling that gave rise to cancer-gene activation.

Lee and Park followed up on that clue by conducting experiments with breast cancer cells in a dish. They exposed the cells to estrogen and then used CRISPR gene editing to make cuts to the cells’ DNA.

As the cells mended their broken DNA, they initiated a repair chain that resulted in the same genomic rearrangement Lee and Park had discovered in their genomic analyses.

Estrogen is already known to fuel breast cancer growth by promoting the proliferation of breast cells. However, the new observations cast this hormone in a different light.

In light of our results, we propose that these drugs may also prevent estrogen from initiating cancer-causing genomic rearrangements in the cells, in addition to suppressing mammary cell proliferation.

It all started with a single observation. We noticed that the complex pattern of mutations that we see in genome sequencing data cannot be explained by the textbook model. But now that we’ve put the jigsaw puzzle together, the patterns all make sense in light of the new model. This is immensely gratifying.

Jake June-Koo Lee

They show estrogen is a more central character in cancer genesis because it directly alters how cells repair their DNA.

The findings suggest that estrogen-suppressing drugs such as tamoxifen — often given to patients with breast cancer to prevent disease recurrence — work in a more direct manner than simply reducing breast cell proliferation.

The study could lead to improved breast cancer testing. For instance, detecting the genomic fingerprint of the chromosome rearrangement could alert oncologists that a patient’s disease is coming back, Lee said.

A similar approach to track disease relapse and treatment response is already widely used in cancers that harbor critical chromosomal translocations, including certain types of leukemia.

More broadly, the work underscores the value of DNA sequencing and careful data analysis in deepening the biology of cancer development, the researchers said.

For more information on the work of Barbara McClintock, see: The Nobel Prize in Physiology or Medicine 1983. NobelPrize.org. Nobel Prize Outreach AB 2023. Tue. 23 May 2023.

More technical detail is given in the scientists' abstract to their open access paper in Nature:

Copyright: © 2023 The authors.
Published by Springer Nature Ltd. Open access. (CC BY 4.0)

Abstract

Focal copy-number amplification is an oncogenic event. Although recent studies have revealed the complex structure^1,2,3 and the evolutionary trajectories⁴ of oncogene amplicons, their origin remains poorly understood. Here we show that focal amplifications in breast cancer frequently derive from a mechanism—which we term translocation–bridge amplification—involving inter-chromosomal translocations that lead to dicentric chromosome bridge formation and breakage. In 780 breast cancer genomes, we observe that focal amplifications are frequently connected to each other by inter-chromosomal translocations at their boundaries. Subsequent analysis indicates the following model: the oncogene neighbourhood is translocated in G1 creating a dicentric chromosome, the dicentric chromosome is replicated, and as dicentric sister chromosomes segregate during mitosis, a chromosome bridge is formed and then broken, with fragments often being circularized in extrachromosomal DNAs. This model explains the amplifications of key oncogenes, including ERBB2 and CCND1. Recurrent amplification boundaries and rearrangement hotspots correlate with oestrogen receptor binding in breast cancer cells. Experimentally, oestrogen treatment induces DNA double-strand breaks in the oestrogen receptor target regions that are repaired by translocations, suggesting a role of oestrogen in generating the initial translocations. A pan-cancer analysis reveals tissue-specific biases in mechanisms initiating focal amplifications, with the breakage–fusion–bridge cycle prevalent in some and the translocation–bridge amplification in others, probably owing to the different timing of DNA break repair. Our results identify a common mode of oncogene amplification and propose oestrogen as its mechanistic origin in breast cancer.

Lee, J.JK., Jung, Y.L., Cheong, TC. et al.
ERα-associated translocations underlie oncogene amplifications in breast cancer.
Nature (2023). https://doi.org/10.1038/s41586-023-06057-w

Copyright: © 2023 The authors.
Published by Springer Nature Ltd. Open access.
Reprinted under a Creative Commons Attribution 4.0 International license (CC BY 4.0)

It will be interesting to see how this is waved aside by creationists in their struggle to cope with the cognitive dissonance between the real world, and how they would like the real world to be. One thing they will find hard to explain is where 'sin', whether in the form of a second designer, or in the form of a force of some sort, causes the processes they attribute to their putative designer to go wrong and result in suffering. Unless of course, they attribute the breasts of mammals and the whole of cell reproduction to 'sin', so their divine malevolence escapes any culpability for breast cancers.

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