Progesterone receptors and genies of Breast cance : What are The mistaken belief,

Discuss , debate and new developments & finally anlyze what we mean by etiology of Br cancer . Get acquanatied with Progesterone receptors: We frequently prescribe progesterone alone or in combination with Oestrgen as is  in COC. Is such long term progesterone therapy can we induce Breast cancer ?? If so how and to whar extent ??

Ans:-The The progesterone receptor is a single gene expressed in two isoforms: PR-A (94 kDa) and PR-B (116 kDa). There are homodimers (A-A), (B-B) and heterodi­mers (A-B) occurring naturally, in different proportions in different target tissues in the female body. They exhibit distinct transcriptional regulatory functions targeting various subsets of genes . The inactivated receptor is activated by hormone (ligand) binding. This hormone-receptor complex translocates to the nucleus where it binds to specific DNA sequences in the promoter regions of target genes to acti­vate gene expression.

Alternatively, the expression of specific target genes can be repressed through interaction with various transcriptional factors such as nuclear factor kappa p (NFkp). Consequently, the clinical significance of activation of the receptor is critically dependent on the transcriptional co-activators and repressors ,,

PR-A is mainly located in the nucleus. This receptor is required for uterine development. PR-B, which is essential for breast development, continuously shut­tles between nuclear and cytoplasmatic compartments .Both receptors are co-expressed in the same tissues usually in equal ratios.

We have never asked ourselves why:-In humans, normal mam­mary gland function may rely upon the balanced expression of the two PR isoforms. In breast cancer cells, however this ratio is often altered. An imbalance between the two isoforms appears to be linked to different cancerous phenotypes in the breast . PR-A receptors are more stable and less active. PR-B receptors undergo exten­sive cross-talk with mitogenic protein kinases and are therefore heavily phosphory- lated (more often via action of growth factors) .

The PRs can be phosphorylated (and therefore modified) after ligand treatment in response to local growth factors. Mitogenic protein kinase activity is very high in a cancerous environment. They have been shown to persistently phosphorylate, and thus modify PRs action, even in the absence of a ligand. This causes an inappropriate activation of PRs affecting PR modifying binding partners.

Cutting edge topic,

Role of oestrogens in the etiology of Br cancer?? Ans:-The presence or absence of estro­gen has a significant modifying effect on the PR. PR action differs in normal breast tissue compared to neoplastic breast tissue. These effects are also organ spe­cific, proliferating in the breast inhibitory in the endometrium.

 In summary, the PR has complex and versatile actions which are:—(1) different in normal and neoplas­tic tissue. (2) Tissue specific. (3) have different biological clinical actions regarding PR-A and PR-B. (4) May be ER dependent or ER independent. (5) Can act independently without binding ligand (progesterone). (6) different and specific for each progestogen. (7) different if given un a continuous or cyclic fashion. The above effects clearly indicate the varied effects that progestogens have on breast cancer cells biology, but the mechanisms are still not fully elucidated but itt isa equally true that Lack of evidence is not lack of effect.