Changes in the cell cytoskeleton occur in cell transformation and recent data suggest the involvement of ovarian
hormones, which are implicated in
cancer development and progression. In human breast and endometrial
tumors, there is disrupted expression of
progesterone receptor (PR)
isoforms and predominance of one
isoform, usually PRA. PRA predominance is an early event in
carcinogenesis, and in
cancers is associated with poor clinical features. Overexpression of PRA in vitro causes altered
progestin regulation of cell morphology, suggesting that PRA overexpression may provoke deleterious changes in cell functioning. This study aimed to identify pathways of cytoskeleton regulation responsive to
progestins and to determine whether these are perturbed when PRA is overexpressed to the levels seen in
cancers.
Progestin treatment of PR-positive
breast cancer cells caused increased cell surface area whereas after induction of a stably integrated PRA construct, cells became rounded and the cell surface was decreased. The effect of PRA induction on cell rounding was reversed by the anti-
progestin RU38486. Altered
tropomyosin (Tm)
isoforms were implicated in these morphological differences, as there was a PRA-mediated alteration in Tm5
isoform levels, and transfection of Tm5a mimicked
progestin-mediated cell rounding in PRA-overexpressing cells.
Ezrin was redistributed from the membrane to cytoplasmic locations in the presence of
progestin, and discrete focal localization was evident in cells with PRA predominance.
Progestin effects on the cytoskeleton in PRA-overexpressing cells provide evidence for novel endocrine regulation of aspects of actin microfilament composition, suggesting that changes in the cytoskeleton known to be associated with
cancer development and progression may be regulated in part by altered PRA expression which develops early in
carcinogenesis.