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Breast Cancer: The Sleeping Beast Within [Part One]

Breast cancer is the abnormal and uncontrollable growth of cells within the breast, which can become fatal if left untreated.


For most women, the key symptom indicative of breast cancer would be the feeling of a hard, immobile lump on the breast. However, it is still important to note that there are other notable symptoms such as bleeding from the nipple, the presence of redness, and/or dimpling of the breast. These can emerge within any woman from any race, age (provided the woman has hit puberty), or geographical location. In other words, the group at risk of developing breast cancer is, essentially, the entire female population.


To dive into the quantitative aspect of things, breast cancer affects one in eight women and one in 100 men at some point in their lives. These are undeniably staggering statistics, and it probably isn’t too surprising to learn next that breast cancer is actually the leading cause of cancer-associated death in women (with lung cancer in second place).


You might just be wondering – how on Earth could such a condition have developed?


To answer that question, let’s first investigate the molecular components involved in the formation and progression of breast cancer.



But first, a cell biology lesson


The anatomy of the female breast

The breast is made up of milk-producing mammary glands, which are organised into alveolar-like structures called lobules. The lobules produce and secrete milk into ducts, which then carry the secreted milk to the nipple for discharge. Meanwhile, fatty tissue and connective tissue surround the glandular tissue and support the structure of the breast. Crucially, all of these tissues are rich in blood vessels to allow the consistent supply of oxygen, nutrients, and hormones to the cells.


Moving on, the linings of the lobules and ducts are made up of epithelial cells. These cells have receptors for chemical messengers (called hormones) like estrogen and progesterone. Basically, these hormones tell the cells when it is time for secondary sexual organs (including the breast) to develop, and this happens during and after female puberty, where estrogen and progesterone are produced by the ovaries during the menstrual cycle. In the case of estrogen, the milk ducts grow as the epithelial cells in the duct divide in response to estrogen levels. Similarly, progesterone is also involved in initiating the maturation of the lobules, and its levels are at their highest during pregnancy when milk production is inhibited. When the lobules are fully developed, progesterone levels drop sharply and thereby permit lactation (induced by another hormone called prolactin; stimulates milk production).


During breastfeeding, the myoepithelial lining below the epithelium contracts in the presence of another hormone called oxytocin to allow the delivery of milk to the infant.


In breast cancer, the epithelial cells lining the ducts and lobules can undergo malignant transformation, giving rise to a carcinoma.


When these cells divide uncontrollably to the extent where it starts to invade the surrounding tissue, this is defined as invasive carcinoma. In contrast, carcinomas that are still localized within the duct or lobule in which cancer arises are known as in situ carcinomas. The most commonly diagnosed version of breast cancer is invasive ductal carcinoma (making up about 80% of breast cancers). Meanwhile, the second runner-up is invasive lobular carcinomas, which constitute 10% of breast cancers.

Figure 1: An anatomy of the breast, with the location of the ducts and lobules shown. The ducts run from the nipple to the inside of the breast where it branches out into round structures forming the milk-producing lobules, as shown in the box on the right. Both the ducts and lobules are lined with epithelial cells (shown as light pink cells), whilst the myoepithelial lining surrounds the structures (shown as dark pink cells). Both in situ and invasive carcinomas are displayed, with cancerous epithelial cells shown in red. Figure created using BioRender.


A brief introduction to the cell cycle

Healthy cells divide and die as part of a process known as the cell cycle. The process is primarily driven by proteins, with the genes encoding relevant proteins known as proto-oncogenes (i.e. any gene that promotes cell division)


In essence, the cell cycle is a heavily regulated process, whereby the expression of genes is tightly controlled depending on the stage of the process. In order to achieve that, there are multiple checkpoints in place during the entire cycle.


To begin with, the G1 checkpoint acts as the crucial starting point for cell division. It evaluates various aspects ranging from whether the cell has all the necessary nutrients to multiply, to whether the DNA is still undamaged, to whether mitogens are present in the environment to stimulate cell division (we will explore mitogens in a bit). If the answer to these questions is a “no”, the cell will then remain in the G0 phase and not divide. In contrast, if the answer is a “yes”, the cell would then undergo the G1/S transition (the “S” stands for the synthesis of DNA), which involves the replication of DNA.


This DNA replication event (involving the duplication of chromosomes in the nucleus) is essentially an error-prone process. The harmful effects of this are typically mitigated by the presence of two DNA damage checkpoints, namely the S/G2 transition and the G2/M checkpoint. Simply put, they both follow the same criteria as the G1 checkpoint. From there, a cell that contains no errors, or has its errors fixed by essential DNA repair proteins, will continue to move to the G2 phase before eventually entering the M phase.


In the G2 phase, the cell continues to grow and prepare itself for mitosis by synthesising all the components essential for the production of a new cell. As the name “M phase” implies, the cell undergoes mitosis and thereby gives rise to two cells, each with a full set of chromosomes. After that, the cells enter the G0 phase once again and the cycle repeats once it is time to divide again.


Over time, the cell tends to accumulate many harmful and irreparable changes. Upon reaching a point where it cannot go past any of the cell cycle checkpoints, the cell cycle machinery detects this damage through the presence of certain proteins that mediate cell cycle regulation. The cell cycle is then stopped, and proteins like p53 and checkpoint kinases direct the cell to its demise.

Figure 2: The progression of the cell cycle is promoted by upregulating the expression of proto-oncogenes encoding cell cycle proteins like cyclins and cyclin-dependent kinases (cdks). Cdks are omitted for simplicity, but they form complexes with cyclins to allow the proper functioning of cyclins. Conversely, the cycle is regulated by inhibiting cyclins and activating checkpoint kinases (chk). These work to delay the cycle until all the essential components for the new cell are synthesised and the cell is ready to divide again. Other than that, if the cell happens to have incurred damage that is beyond repair, proteins like p53 can stop the cycle and direct the cell to destruction. Figure created using BioRender and adapted from Otto & Sicinski (2017).


The culprits for breast cancer


Non-genetic factors

Misregulation occurs when mitogens bind to their receptor for too long and the proto-oncogene is transcribed beyond what is needed for a normal cell cycle.


This alteration of gene expression is studied in a broad discipline called epigenetics. To help illustrate epigenetics, you can imagine how cells in the gut and cells in the breast of the same organism are extremely similar in terms of their genetics. However, they each have very different functions, protein make-up, and hence, gene expression profiles. The differences in the gene expression essentially boil down to the epigenetics of the cell, which involves non-genetic changes like selective DNA methylation (the reversible attachment of the hydrocarbon group, -CH3, to sites on the DNA) and histone modifications.


These changes are regulated by external factors like the presence of mitogens, hormones, bioactive food compounds, or chemicals in the environment. And most importantly, they can be deregulated in cancer. In particular, while the DNA remains unchanged in terms of its nucleotide sequence, these external factors can cause the methylation of DNA at specific sequences for instance. As a result, this can either enhance or inhibit gene expression at varying degrees.


To give you an example, estrogen can bind to the estrogen receptors (ER) within breast epithelial cells. This causes the demethylation of regulatory DNA sequences that are found next to specific target genes, and in doing so, it activates the transcription of their target genes (i.e. the proto-oncogenes that promote proliferation). Meanwhile, progesterone can achieve the same effect as well by binding to the progesterone receptor (PR). In the event when estrogen or progesterone binds to their respective receptors over an extended period of time, too much protein will be produced, and this can drive uncontrolled proliferation (See Footnote 1 for something important).


Taking that into account, we can now see why an estimated 70% of breast cancer cases are caused by prolonged estrogen exposure, with factors contributing to this including early menarche (meaning an early onset of menstruation), late menopause, hormone replacement therapy, and even alcohol consumption.


Genetic factors

All cells have the genetic tools required to proliferate, but they can be easily mutated. Hence, these alterations may result in the cells eventually being able to proliferate uncontrollably. Unlike epigenetic changes, mutations within the genome are much more heritable and non-reversible, and that is where the ultimate danger lies.


Proto-oncogenes can get mutated

Mutations can be introduced within the genome and this alters the way genes are expressed. They are typically caused by cancer-causing agents called carcinogens, with examples of such agents including chemical compounds (such as those found in cigarette smoke or alcohol) and ionizing radiation.


Mutations can have an activating or silencing effect. If the activating mutation occurs within a regulatory sequence that is located next to the proto-oncogene, the altered sequence can promote overexpression of the gene. This gives rise to an oncogene. On the other hand, silencing mutations do not activate an oncogene. So, if the gene is silenced, the cell would not proliferate.


Besides that, carcinogens can also induce random mutations within the proto-oncogenes, thus changing the core information to be read. Should the mutation be activating (a.k.a a gain-of-function mutation), the protein that gets synthesised would be hyperactive and hence promotes greater proliferation. In fact, some studies have proposed that these proteins may even be resistant to degradation.


Various research has shown that the ERBB2 proto-oncogene, when mutated, gives rise to an active oncogene responsible for approximately 30% of breast cancer cases. In particular, the ERBB2 oncogene encodes the Human Epidermal Growth Factor Receptor-2 (Her-2; a receptor for mitogens), which is expressed on the cell surface and acts as a useful biomarker for breast cancer.


Tumour suppressor genes can get mutated

In a normal situation, a healthy cell “senses” the DNA damage caused by mutations and activates protective, anti-proliferative mechanisms conferred by tumour suppressor genes. Tumour suppressor genes code for proteins that can counter the stimulation of cell cycle proteins and stop the cell cycle (this process is termed “cell cycle arrest”), repair damaged DNA, and induce programmed cell death (known as apoptosis). In short, we can technically say that any gene which antagonises cancer and slows down cell division is a tumour suppressor gene.


However, there are times when a cell can evade death, maintain its damaged and/or mutated form, and continue to proliferate. They usually achieve this by having either loss-of-function mutations in the tumour suppressor gene or possessing strong proliferative signalling that can effectively outweigh anti-proliferative signalling.


In general, the universally mutated tumour suppressor gene seen in many cancers is the p53 gene. But if we were to narrow it down to breast cancer, the two main tumour suppressor genes that often get disrupted are BRCA1 and BRCA2, whereby both of these genes code for DNA repair proteins.


Nevertheless, it is still intriguing to know that even though women who inherit mutated versions of BRCA1 and BRCA2 are at significantly increased risk of developing breast cancer during their lifetime, this demographic only accounts for 5% of breast cancer cases. Other than that, another interesting observation is that mutations in these genes also increase the risk of ovarian cancer.

Figure 3: From mitogen signalling to the cell cycle (mRNA translation is omitted for simplicity). This proto-oncogene-to-oncogene transformation step is central to many cancers – breast, prostate, ovarian, you name it! Left: The normal expression of the proto-oncogene is regulated by the binding of a mitogen to its receptor and the consequent interactions by the messenger protein. Right: (a) The prolonged stimulation of the mitogen receptor can lengthen the activation of the oncogene. (b) Mutation in the regulatory sequence can enhance the expression of an oncogene. (c) Mutation in the proto-oncogene can transform the proto-oncogene to an oncogene by encoding a higher activity protein. (d) In a healthy cell, the tumour suppressor gene would be activated, and it performs functions like repairing mistakes in the DNA, arresting the cell cycle, or inducing apoptosis. (e) In cancer, tumour suppressor genes are often inactivated. And in fact, these loss-of-function mutations can contribute more to the progression of cancer than gain-of-function mutations in the oncogene. Figure created using BioRender.


Our own body messes up as well

While cancer is seen by some to be a random deadly mutation event that occurs within a single cell, it is also important to note that as a disease, cancer arises from the failure of our body to defend itself. To further elaborate, our immune system constantly suppresses cancer by targeting and killing individual cancer cells. So, when cancer cells escape this attack, they can proliferate to form a tumour at the site.


Generally, we can classify tumours as either benign (non-invasive) or malignant (invasive).


The key thing to note is that only malignant tumours are implicated in cancer as they show the potential to spread beyond the tissue of origin. Benign tumours, on the other hand, are typically not life-threatening and often remain localized to a specific region in our body.


You may also find it reassuring that the majority of breast lumps reported by women are actually caused by benign tumours. Therefore, if you do observe a mass in your breast, it should not immediately be a cause for panic and the most appropriate action for you is to consult your doctor right away.


The stages of breast cancer

You could equate breast cancer to some sort of time bomb, for it can be categorised into Stages 0 to IV with the five-year survival rate of patients decreasing from 99% (Stage 0-II) to 86% (Stage III) to 27% (Stage IV) as cancer progresses.


It starts as a small, harmless, and localized carcinoma, where it then steadily progresses to its invasive forms whilst releasing substances to stimulate the growth of blood vessels towards the tumour in a pathological process known as angiogenesis. This supplies oxygen and nutrients to the cancer cells, thereby allowing the tumour to continue its growth.


Finally, its lethality manifests itself in a process known as metastasis, in which the cancer cells gain motility and can travel through the blood vessels or the lymphatic system to distant parts of the body (such as the liver).

Figure 4: The different stages of breast cancer (shown in the invasive ductal carcinoma type), from Stage 0 to Stage IV. When the epithelial cells in the breast continue to divide uncontrollably and escape death, they constitute an abnormal mass of cells called a tumour (as seen in Stage 0). As cancer progresses from Stages I to III, these malignant cells can divide and grow past the epithelium, invading tissue surrounding the ducts or lobules. Following that, in Stage IV, these cells can further migrate through blood vessels or the lymphatic system to distant tissue (such as those in the lungs). Figure created using BioRender and adapted from Chen et al. (2018).


What can we do for ourselves?

As we can see, breast cancer is clearly a complex disease that is influenced by a multitude of factors whose detrimental effects accumulate over time.


To defeat the beast within, we can detect breast cancer early, and this is done through performing a monthly breast self-exam (BSE). This helps you to become better acquainted with the normal size and shape of your breasts so that you can identify changes and report them to your doctor if anything strange emerges (for example, if you find a lump or notice a dimpling in your breast).


There are various resources online to help guide you through one, and this is of paramount importance as the earlier the breast cancer is detected and treated for, the better the outcome. Meanwhile, for women at high risk or aged 40 and above, annual mammograms are highly recommended as not all lumps can be felt.


Furthermore, we also need to effectively reduce the extrinsic stress we place on our bodies. Such stress can include exposure to mutagenic carcinogens through smoking or excessive alcohol consumption. In essence, by adopting lifestyle changes such as quitting smoking, eating healthily, and exercising regularly, we strengthen our body to fight against various types of cancer. On top of those, some of the less well-known actions we could potentially take to protect ourselves from breast cancer are to breastfeed over a longer duration or bear children early (though bear in mind that the relationship between these and breast cancer risk is still being studied).


Moving forward, we will focus on the molecular subtypes of breast cancers in our next article as part of the series, whereby they are categorised based on the receptors they express – namely, the estrogen receptor, the progesterone receptor, and the Her-2 receptor. It is important to address this aspect as doctors and researchers use this classification to measure the “aggressiveness” of cancer, and consequently, decide on the best treatment to administer to patients.


Footnote

  1. It is key to note that while estrogen and progesterone do exert a mitogenic effect on breast cells, whether or not they can be called mitogens is unclear as mitogens are typically proteins (while estrogen and progesterone are steroid hormones).


Author


The Yana Project is a society consisting of Malaysian students passionate about helping breast cancer and ovarian cancer patients and survivors. We aim to promote awareness on the risks of breast cancer and how to reduce them, create a platform that encourages an open discussion on these topics along with actively showing emotional care and support for patients and their loved ones. Do visit @the.yana.project on Instagram to find out more about what we do – psst; we have helpful infographics on how to perform a self-examination, for both women and men!


  • Lutfir Hamzam, BSc Biochemistry with French for Science, Imperial College London


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