Women exposed to exogenous
progesterone have increased
breast cancer risk, but the mechanisms of
progesterone involvement in
breast cancer development are unknown. In human breast and endometrium,
progesterone receptor (PR)
isoform expression is disrupted in premalignant lesions and predominance of one
isoform, usually PRA, in invasive
cancers is associated with poorer prognosis. Disrupted PR
isoform expression results in disrupted
progestin regulation of cell morphology, including rounded morphology and decreased adherence of cells to tissue culture flasks. The purpose of this study was to test the hypothesis that predominance of PRA affects the interaction of
breast cancer cells with a physiologically relevant stromal tissue, bone marrow stroma. T-47D
breast cancer cells demonstrated the ability to migrate into bone marrow fibroblasts and this was inhibited by
progestin treatment. The antiprogestin
RU38486 abrogated the
progestin effect on migration, demonstrating that it was PR-mediated. In cells expressing a predominance of PRA, after induction of a stably integrated inducible PRA construct, the ability of
progestin to inhibit
breast cancer cell migration was lost. A number of
integrins were
progestin regulated in T-47D cells, but there was no difference in the
progestin effect in cells with PRA predominance, nor were the levels of focal adhesion
proteins altered in these cells. This suggested that the lack of inhibition by
progestin of
breast cancer cell migration in cells with PRA predominance was not mediated by PRA effects on the membrane components of the adherens junctions. In summary, this study has shown that PRA predominance has a striking functional effect on
breast cancer cell migration into stromal layers. PRA predominance may render
breast cancer cells relatively resistant to the inhibitory effects of
progestins and one consequence of this may be increased invasion of stroma. If borne out in vivo, these findings suggest that tumours with PRA predominance may be predisposed to
cancer progression and this may signal a poorer prognosis in patients.