Breast cancer in low-middle income countries: abnormality in splicing and lack of targeted treatment options

Abstract

Breast cancer is a common malignancy among women worldwide. Regardless of the economic status of a country, breast cancer poses a burden in prevention, diagnosis and treatment. Developed countries such as the U.S. have high incidence and mortality rates of breast cancer. Although low incidence rates are observed in developing countries, the mortality rate is on the rise implying that low- to middle-income countries lack the resources for preventative screening for early detection and adequate treatment resources. The differences in incidence between countries can be attributed to changes in exposure to environmental risk factors, behaviour and lifestyle factors of the different population groups. Genomic modifications are an important factor that significantly alters the risk profile of breast tumourigenesis. The incidence of early-onset breast cancer is increasing and evidence shows that early onset of breast cancer is far more aggressive than late onset of the disease; possibly due to the difference in genetic alterations or tumour biology. Alternative splicing is a pivotal factor in the progressions of breast cancer. It plays a significant role in tumour prognosis, survival and drug resistance; hence, it offers a valuable option as a therapeutic target. In this review, the differences in breast cancer incidence and mortality rates in developed countries will be compared to low- to middle-income countries. The review will also discuss environmental and lifestyle risk factors, and the underlying molecular mechanisms, genetic variations or mutations and alternative splicing that may contribute to the development and novel drug targets for breast cancer.

Keywords: BRCA; Breast cancer; ER; HER2; aberrant splicing; family history.

Figure 1

Global breast cancer incidence. Age-standardized rate (ASR) for breast cancer incidence including all ages [194].

Figure 2

Global breast cancer mortality. Age-standardized rate (ASR) for breast cancer mortality including all ages [194].

Figure 3

Schematic representation of the BRCA pathway. BRCA1/2 interacts with numerous proteins in response to DNA damage. A mutated BRCA1/2 can lead to genomic instability resulting in cancer [115].

Figure 4

Mechanism of PARP inhibitors and tumour selective synthetic lethality [108].

Figure 5

The alternative splicing of genes with isoforms that play a role in the development and progression of breast cancer. A. BRCA1 is alternatively spliced resulting in truncation or omission of exon 11. B. TP53 is alternatively spliced to give rise to a number of isoforms. Omission of exons coding for the DNA binding domain give rise to isoforms that function as negative regulators of TP53. C. Survivin is alternately spliced to give rise to an isoform that lacks exon 3. D. DMTF1 is alternatively spliced to give rise to an isoform lacking exon 7 which codes for one of the SANT domains. These domains allow interaction with histones to facilitate chromatin remodelling. E. KLF6 is alternately spliced to give rise to isoforms without exon 3 or with a truncated exon 2 which lacks the nuclear localisation signal. F. HER2 is alternatively spliced to give rise to isoforms lacking exon 20. This disrupts the Tyrosine kinase phosphotransferase domain.

Figure 6

Spliceosomal proteins whose expression increases the risk of developing breast cancer. A. The hnRNPs that are oncogenic in terms of breast cancer development include hnRNPA, hnRNPK and hnRNPM. B. The SRSF proteins that are oncogenic in terms of breast cancer are SRSF1, SRSF2, SRSF3 and SRSF5. C. The structure of hnRNPK differs due to the presence of the KH domains rather than RRM domains. None of these pro-oncogenic hnRNPs contain zinc finger domains or Aspartame glutamine acidic domains. The oncogenic SRSF proteins contain only RRM domains and relatively short RS domains.