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Breast Cancer: The Deeper Story

Imagine historians coming up to you saying that there have been records of prevalence of breast tumours in ancient medicine scriptures of Papyrus. Imagine being in the year 1882 and being able to witness William Halsted perform the first radial mastectomy, which continued to be the standardized method of treating breast cancers until the 20th century. Since then, we have come a long way right from research in discovering putative oncogenes to implementation of advanced, therapeutic methods into rehabilitation of those affected by breast cancer. Medical associations presenting the status quo of this disease have shown that even though the overall mortality rate for breast cancers has significantly declined over the last decade, it still is one the most common types of cancers diagnosed in women and has even taken invasive manifests in the more recent cases.

Breast cancer, like any other cancer fulfils certain hallmarks of oncogenic development, most primarily being unregulated proliferation of the cells in the glandular tissues of the breasts, leading to the development of a tumour, which initially benign, can become metastatic due to epithelial to mesenchymal transition of cancer cells from the glandular ducts and lobules to the surrounding connective tissue and eventually to the bones, brain, lungs and liver. The pathophysiology and causative triggers are multidimensional and poorly comprehended, but certain risk factors are often highlighted. While certain risk factors like advancing age, female sex orientation, high body mass index (BMI), extension of menstrual cycles, administration of hormone altering medications are deduced from the statistics of occurrence of this disease, two factors have often been extensively studied regarding the inducive activity for development of breast cancer: Genetic mutations in BRCA1 and BRCA2 genes and HER2/neu, ErbB2, PGR and ESR1/ ESR2 genes respectively.

The BRCA1 and BRCA2 genes are both tumour suppressor genes (TSGs), intrinsically present in humans. Though both are structurally unrelated, having their loci on the 17th and 13th chromosomes respectively, their functions are intertwined, predominantly being involved in DNA repair. BRCA1 gene combines with other TSGs, DNA damage sensors and signal transducers to form a surveillance complex, which keeps a check on mutation due to DNA damage. It was earlier known to have a major role in transcriptional regulation by associating with RNA Polymerase II. However, later research after protein fractionation indicated that the BRCA1 protein co-purified with a chromatin remodeling complex SWI/SWF. It mostly indicated that it could interact with histone acetylase/deacetylase complexes, i.e. ones which are responsible for histone acetyl modifications and change the structure of chromatin (Remember chromatin = DNA + histone proteins). BRCA2 gene investigation is relatively unchartered and the only independent known function of this gene to be studied is that it helps in protection of replication forks by preventing its nucleolytic degradation by the MRX protein complex. In unison, both the BRCA genes are responsible for maintenance of strand invasion during homologous recombination along with RAD51 recombinase. The oncogenic mutations primarily observed by throughput screening analyses are nonsense, frameshift, and splicing mutations. There are multiple theories surrounding the actual nature of mutations some of which including epigenetic control systems like hypermethylation of promoters for these genes and variation in the miRNAs binding with the 3′ UTR of the BCRA mRNA. These genetic mutations form the basis for hereditary influence of breast cancer and are accentuated when family members are diagnosed with the same.

BCRA 1 protein BCRA 2 protein

BCRA mediated strand invasion

In case of non-metastatic breast cancer, hormone receptivity is one of the most common traits observed. This has primarily gained momentum not only as a biomarker assay by immunohistochemistry, but also for targeting the cancer cells as a therapeutic measure. Three types of genes are chiefly investigated under this category: ErbB2, PGR and ESR1/ ESR2genes. Each of these genes are responsible for the presence of specific receptors which form a salient criteria for classification of cancers for the administration of drugs accordingly. ErbB2 or also called HER2, belongs to the family of epidermal growth factor receptors in humans and has actively been studied over the years to be determined as an oncogene whose over-expression can lead to breast cancers.

The amount of these receptors on the surface of the cancer cells in many ways determines the prognosis of the disease. For eg: Triple-negative breast cancer refers to malignancies that do not express hormone receptivity or HER2. PGR and ESR1/ ESR2 genes are also notably significant, innately coding for progesterone (PR) and estrogen receptors (ER), respectively. While the function of ESR2 is still cryptic, it is hypothesized that single nucleotide polymorphisms in ESR1 and PGR genes contribute to oncogenic development. The molecular mechanisms for ER driven tumourigenesis are believed to be that binding of estrogen to ER promotes cell proliferation and has an augmented probability of inducing mutation. Another very popular theory that drives this wagon is that the metabolism of estrogen produces genotoxic wastes, i.e. substances which can alter the genotype.

Tamoxifen was the first FDA approved drug to treat breast cancers. They act as ER antagonists and modulate the binding of estrogen onto them. While PR and progesterone molecular mechanisms have not been illustrated very distinctively, their role in cancer development is often studied synergistically to ER mediated responses. But recently, a startling discovery changed this paradigm of complementarity because it was shown how administration of progesterone can reprogram the ER binding to many other regulatory elements, resulting in changes in gene expression profile and ultimately leads to cell cycle arrest.

Tamoxifen tablets

While the current methods of therapy including radiation, chemotherapy and surgical mastectomy are most popularly employed, there is indeed scope for advanced therapeutic methods to flourish. One such example, quite relevant to aforementioned context, is the use of monoclonal antibodies (MAbs) which are a custom made antibody that only attaches to a specific epitope. Now since they are synthesized in vitro, why limit them to just antigens? Hence, active research is going on to branch out with the utility of these MAbs to be used in multiple combinations, with other biomolecules to target other pathogens like viruses. In terms of breast cancer treatment, the MAb trastuzumab has successfully been harnessed to bind to HER2 receptor which is shown to stimulate the downstream response of elevating the amount of p27, a protein that halts cell proliferation.

Trastuzumab MAb

Production of monoclonal antibodies

Even though the mortality rates due to breast cancer have decreased as mentioned initially, it is alarming how our lifestyles and novel oncogenic triggers that are being unearthed regularly, are contributing to the rise of incidence of this disease. Hence, it is essential that women above 50 get regularly checked and follow a low-risk regimen. Breast cancer awareness is the need of the hour and requires the attention of people to incentivize the commencement of a revamped, contemporary effort to invest in the research and development for the same.

- written by Sanjana Balaji

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