Breast cancer:-Breast Cancer: The Progesterone Effect

Breast cancer is the most common tumor in women. The life time risk of developing breast cancer is 12 %. Most of the neoplasms present after the menopause and the incidence rises sharply with age. Approximately 5-8 % of tumors arise due to a hereditary predisposition e:g, BRCA-1 mutation.

Most breast cancers are initially hormone dependent with estrogen playing a crucial role in development and pro­gression. Breast cancer may develop very slowly having a mean doubling time of 90 days. After a period that may last several years, many breast cancers become hor­mone independent .. Hormone independence may be due a mutation in the estro­gen receptor.

Breast cancers are subdivided into two major subtypes:- 1.) Luminal, estrogen receptor positive (ER+), progesterone receptor positive (PR+), cytokeratin 18 posi­tive (CK18+). These tumors make up approximately 80 % of all breast cancers.

2.) Basal ER-, PR-, CK5+. These tumors have a much worse clinical prognosis ..In the human breast, normal stem cells are found. They can be defined by expression of epithelial specific antigen (ESA) and «6-integrin. Some believe that ER+ /PR+ luminal cancer cells arise from distinct ER+/PR+ stem cells However, in recent years it was discovered that in solid ER+/PR+ experimental tumors, CK5+ cells persist that are ER-/PR- stem cells that are actually up regulated by progestins These colonies, though small in size (up to 100 or less cells) expand and can differentiate into the more common ER+/PR+/CK5-,tumors. Approximately, 2 % of cells in these receptor positive breast cancers retain the ER-/ PR-/CK5- stem like signature. Treatment of ER-/PR-/CK5+ colonies with pro­gesterone, but not with estrogen, leads to an increase in the ER-/PR-/CK5+ stem cell subpopulation from 1 to 2 % to over 20 %. MPA (medroxy-progesterone ace­tate) has been found to have a more significant effect than other progestins. This increase is independent of estrogen. Hence, it seems that tumor cells can regress from a differentiated state to a more stem-like state, in response to progestins. Reactivation of the CK.5+ cells (with strong CK18 expression, proving it to be of luminal origin) by 24 h of MPA exposure is usually more pronounced in the younger recently formed tumors.

The culprit is the intermediary product namelu 5a-pregnane ::--In tumor tissue, the concen­tration of mitogenic 5a-pregnane was 14 times that of the anti mitogenic 3a-HP. In contrast, in the adjacent normal breast cells, the concentration of antimitogenic 3a-HP was more than three times that of the mitogenic 5a-pregnane In view of the fact that 5a-P stimulates cell proliferation and metastasis, while 3a-HP and 20a-HP exert an antimitogenic effect, increasing apoptosis and cell adhesion, treatment with progesterone may stimulate cell growth only in the presence of malignant breast tissue

 In contrast, in normal breast cells, 5a-reductase activity is low. However, other enzymes, namely 3a-hydroxysteroid oxidoreductase and 20a-hydroxysteroid oxidoreductase metabolize progesterone to 3a-dihydroprogesterone (3a-HP) and 20a-dihydroprogesterone (20a-HP). These Local Production and Action of Progestins:- pharmacological properties of progestogens vary according to the parent molecule front which they are derived (testosterone, progesterone, aldosterone etc.) This, together with their ability to activate or deactivate related glucocorti­coid receptors, mineralocorticoid receptors and androgen receptors is the reason for the different biological activities specific to each progestogen . The enzyme, 5a-reductase, converts progesterone to 5a-pregnanes (e.g. 5a-dihydro- progesterone= 5a-P). 5a-reductase is highly expressed in cancerous cells but not in normal breast cells. 5a-P which is mainly produced by the cancerou5a-pregnane s cells stimulates cell proliferation and metastasis via activation of the MAP-kinase path­way.

metabolites exert an anti-mitogenic effect and increase apoptosis and cell adhesion... In tumor tissue, the concen­tration of mitogenic 5a-pregnane was 14 times that of the anti mitogenic 3a-HP. In contrast, in the adjacent normal breast cells, the concentration of antimitogenic 3a-HP was more than three times that of the mitogenic 5a-pregnane In view of the fact that 5a-P stimulates cell proliferation and metastasis, while 3a-HP and 20a-HP exert an antimitogenic effect, increasing apoptosis and cell adhesion, treatment with progesterone may stimulate cell growth only in the presence of malignant breast tissue

Take home message :-It can be concluded that progestins, acting via their progesterone receptor affect the more abundant ER+/PR+/CK5 differentiated cells to reactivate ER-/PR-/ CK5+ stem cells. It seems that progestogens have the ability to restore cancer stem cell like properties to some ER+/PR+ breast cancer cells. Only after this effect takes place, can estrogen resume growth and proliferation of the stem cells to expand ER+/PR+/CK5- breast tumors.

The Both ER/PR positive and ER/PR negative breast tumors are able to convert pro­gesterone to 3a-HP. Specific high affinity membrane receptors exists for both 5a-P and 3a-HP. These receptors are completely distinct not only from each other but also from known ER, PR, AR and corticosteroid receptors [26]. Levels of 5a-P receptors are up-regulated by 5a-P and estradiol, and down-regulated by 3a-HP in both ER/PR positive and negative tumor cells [28]. 5a-P and 3a-HP have opposing effects on initiation and growth of ER/PR negative human breast tumors. These metabolites, which are independly produced by breast cancer cells, underscore the importance of the microenvironment in regulating expression of receptors, adhesion molecules, growth promoters and inhibitors within the breast cancer cells. 3a-HP maintains normal breast tissue. It inhibits proliferation, tumor initiation and tumor growth. 5a-P has exactly the opposite effects. It induces proliferation, tumor growth and detachment and reduces apoptosis.