What is RANK/RANKL in Breast cancer and Progesterone

RANKL—is “receptor activator of the NF-kp ligand”

RANKL—receptor activator of the NF-kp ligand is highly expressed in human breast cancer cells. RANK and its ligand RANKL are expressed in preinvasive mammary intraepithelial neoplasia and invasive carcinoma of the human breast. The dividing epithelial cells do not contain ER or PR, but are controlled by adjacent resting cells containing sex steroid receptors which secrete various growth factors, of which RANKL emerges as a key paracrine mediator of the progesterone mitogenic signal. It has been shown that progesterone-knock-out (PRKO) mice mammary epithelial cells, when mixed with wild-type (WT) cells, contribute to alveolar and ductal side branching in the pregnant state. This sug­gests a paracrine factor transmitted from the wild-type breast cells and received by the knock-out cells causing them to proliferate. This paracrine factor was found to be RANKL

Mammary RANKL is induced by exogenous progesterone. In the proliferative phase of pregnancy (in which progesterone is at its peak action driving mammary epithelium expansion and morphogenesis), RANKL is markedly expressed. RANKL expression is confined to ER+/PR+ transmitters’ cells ..Consequently RANKL may act as the direct link between breast cells via progesterone. Finally, evidence that RANKL has a mediator role in mammary progesterone signaling, came from a study where PRKO mammary epithelial cells were transplanted into the mammary fat pad of WT mice. RANKL triggered mammary side-branching and alveolar budding in the PRKO transplant within the pregnant WT host .

It has been demonstrated that the RANKL transduction axis is actually essential for pro­gesterone promotion of mammary tumorigenesis In these studies MPA (medroxyprogesterone acetate), the progestin used in the WFII study, significantly increased RANKL expression in the ER+/PR+ cell population, in mammary normal epithelium as well as in premalignant and malignant cells. Therefore it is evident that progesterone (as well as MPA) relies on RANKL as a paracrine mediator for its proliferative effects. RANKL also enables the mammary epithelium to evade premature apoptosis.

Progesterone and E-Cadherin

E-Cadherin is an epithelial adhesion protein, which is an important, if not the major, component of the tight junctions between mammary epithelial cells. It has been shown that decrease, or loss, of the E-Cadherin protein is associated with tumor cell metastasis and invasiveness, and a poorer prognosis in breast cancer patients [41], E-cadherin protein is highly expressed in normal epithelial cells adjacent to the breast tumors. In an experimental rat model, treatment with E + the R5020 (promegestrone) decreased the levels of E-cadherin precursor and mature E-cadherin protein. This effect was abolished by the progesterone antagonist mifepristone (RU486), implying that the effect is due to the progestin component. In this rat model E + P treatment, as compared with E alone resulted in invasive mammary cancers accompanied by decreased E-cadherin levels and expansion of cells with a basal/myoepithelial phenotype. Similar findings have been observed in invasive pri­mary human breast cancers compared to matched carcinoma in situ. While estrogen alone is sufficient to induce luminal noninvasive tumors, progesterone is required for the expansion of basal-myoepithelial tumor cells that frequently express proges­terone receptor B. Progesterone promotes expansion of the more invasive basal/ myoepithelial cells via direct activation of progesterone receptor B. It is important to note that only progesterone receptor B mediates the effect of progestins on E-cadherin. The ratio of progesterone receptors A/B is almost equal in normal breast tissue. But this ratio is completely altered, in favor of more B receptor in cancerous breast cells.