Ashok Subramanian

Oestrogen producing enzymes and mammary carcinogenesis: a review.

There is a large and compelling body of epidemiological and experimental evidence that oestrogens are instrumental in the aetiology of breast cancer. Their mechanisms of action are varied, including stimulation of cellular proliferation through receptor-mediated hormonal activity, increasing genetic mutation rates through cytochrome P450-mediated metabolic activation, and induction of aneuploidy. The local biosynthesis of oestrogens especially in postmenopausal women is believed to play a very important role in the pathogenesis and development of hormone dependent breast carcinoma and the over-expression of regulatory enzymes seems to be associated with the development of a more aggressive disease and associated with poor outcome and increased local and distant recurrences. In this article we highlight the role of CYP19 gene expression and aromatase activity in mammary carcinogenesis. Other oestrogen producing (17-β-hydroxysteroid dehydrogenase and steroid sulphatase) and catalyzing enzymes (3-β-hydroxysteroid dehydrogenase, Oestrogen sulfotransferase, CYP1A1, CYP1B1, and CYP3A4) are also discussed in some detail. Understanding the mechanisms that regulate these enzymes is crucial to the development of new endocrine therapies in post-menopausal females with hormone dependant breast cancer. Currently, third generation aromatase inhibitors has revolutionized the treatment of oestrogen dependant breast cancer. However, the important role of both STS and 17-β-HSD type 1 in local oestrogen production provides novel potential targets for endocrine therapy. Such endocrine therapy is currently being explored and the development of STS inhibitors, combined aromatase/steroid sulfatase inhibitors and 17-β-HSD type 1 inhibitors is underway with promising initial results.

Lymphangiogenesis and lymph node metastasis in breast cancer

IntroductionThere have been few studies on lymphangiogenesis in the past due to the lack of specific lymphatic endothelial markers, and lymphatic-specific growth factors. Recently, these limitations have been relieved by the discovery of a small number of potential lymphatic-specific markers. The relationship between lymphangiogenesis and regional or distant metastasis has not previously been investigated in humans. Using these lymphatic markers, it is possible to explore the relationship between lymphangiogenesis and tumour metastasis. This study indirectly quantified lymphangiogenesis by measuring mRNA expression of all seven lymphatic markers described above in breast cancers and correlated these markers with lymphatic involvement and survival.The cDNA from 153 frozen archived breast samples were analysed with Q-PCR for all seven lymphangiogenic markers. This was correlated with various prognostic factors as well as patient survival.ResultsThere was significantly greater expression of all 7 markers in malignant compared to benign breast tissue. In addition, there was greater expression in lymph node positive/grade 3 tumours when compared to lymph node negative/grade 1 tumours. In 5 of the markers, there was a greater expression in poor NPI prognostic tumours when compared to favourable prognostic tumours which was not statistically significant. There was no association between recurrence risk and lymphangiogenic marker expression.ConclusionIn summary, the findings from this study show that lymphangiogenesis, measured by specific lymphatic marker expression, is higher in breast cancers than in normal breast tissue. Secondly, breast cancers which have metastasised to the regional lymphatics show higher expression compared to those which have not, although the individual differences for all five markers were not statistically significant.

Insulin-like growth factor binding proteins and breast cancer

The insulin-like growth factor (IGF) axis plays a key role in the growth, differentiation and proliferation of mammalian cells and although vital in many organ systems, has been shown to play a particular role in the normal development of the human mammary gland and has also been heavily implicated in mammary carcinogenesis [1, 2]. The IGF axis comprises two growth factors (IGF-I and IGF-II), their receptors (IGFR-I and IGFR-II) and a group of IGF-binding proteins (IGFBP-I–VII). Both IGF-I and -II bind to IGFR-I although IGF-II also binds to IGFR-II with high affinity. Together, these factors interact to influence cell-signalling pathways which control the eventual growth, proliferation, differentiation and eventual survival of their target cell. IGF-I and -II are both single-chain polypeptides (7 kDa) which share 62% amino acid homology. Although both ligands have affinity for both receptors, the IGFR-I is by far the more active [3]. The eventual action of the IGF ligand is modulated by interaction with a family of seven IGF binding proteins (IGFBP-I–VII) which share 40–60% amino acid homology. The majority (97%) of serum IGF-I is bound to these BPs (particularly to IGFBP-3) which binds the ligand with an affinity equal to or greater than the IGF-IR [4]. The action of the IGF binding proteins is primarily to regulate the bioavailability of the IGF-1 ligand in the circulation and thereby its eventual action at the receptor, but as will be seen, they also have other IGF-dependent and -independent actions at the cell surface which are equally important. Recent evidence, however, strongly suggests that the binding proteins have a ligand-independent action at the cellular level acting via independent receptors both at the cell surface and possibly also at the nucleus. Following the interaction of the IGF ligand with its cell surface receptor, a series of conformational changes and downstream signalling pathways are activated which act to translate this interaction into the eventual cellular effect. This process of cell signalling is vital for the maintenance of normal growth, differentiation and cell survival. However, when a cell develops the malignant phenotype, the signalling pathways often become overactive, under-active or inappropriate resulting in the neoplastic process.

The prognostic significance of the insulin-like growth factor-1 ligand and receptor expression in breast cancer tissue

Previous in vitro studies have suggested that IGF‐1 stimulation can lead a more aggressive breast cancers and subsequent poor prognosis in breast cancer patients. We aim to how IGF‐1 and IGF‐1R mRNA levels in breast cancer are associated with disease‐free survival (DFS) and other clinicopathological factors.

The role of Herceptin in early breast cancer

Herceptin is widely regarded as the most important development in the treatment of breast cancer since Tamoxifen and the development of the multidisciplinary team (MDT). It is particularly exciting from an oncological polint of view as it represents success in the emerging field of specific targeted therapies to specific molecular abnormalities in tumour cells. This review will focus on the nature of the Her2 overexpression and the role of herceptin in the treatment of early breast cancer.