Vl. Seewaldt et al., Human papillomavirus type 16 E6 inactivation of p53 in normal human mammary epithelial cells promotes tamoxifen-mediated apoptosis, CANCER RES, 61(2), 2001, pp. 616-624
Aberrant p53 expression is frequently observed in mammary epithelial cells
obtained from women at high risk for developing breast cancer and is a pred
ictor for the subsequent development of malignancy, Tamoxifen has recently
been shown to reduce the incidence of noninvasive breast cancer in high-ris
k women, but the molecular mechanism of tamoxifen chemoprevention in mammar
y epithelial tissue that does not overexpress the estrogen receptor is poor
ly understood, We suppressed p53 expression by retroviral-mediated expressi
on of human papillomavirus type-16 E6 protein (HPV-16 E6) in human mammary
epithelial cells (HMECs) to develop an in vitro model of tamoxifen chemopre
vention in the context of p53 loss. Early passage p53(-) HMEC-E6-transduced
cells treated with 1.0 muM tamoxifen rapidly underwent apoptosis, In contr
ast, early passage p53(+) HMEC-LXSN vector controls treated with 1.0 muM ta
moxifen underwent G(1)-G(0)-phase arrest but did not undergo apoptosis, p53
(-) HMEC-E6 cells rapidly acquired resistance to tamoxifen-mediated apoptos
is after 10 passages in culture (in the absence of tamoxifen), Both p53(+)
and p53(-) HMECs exhibited a low level of estrogen receptor staining and mi
nimal estrogen binding, characteristic of proliferating normal luminal mamm
ary epithelial cells, Tamoxifen-mediated apoptosis in p53(-) HMEC-E6 cells
was not blocked by inhibitors of transcription and protein synthesis, These
data suggest that the acute loss of p53 function in HMECs by expression of
HPV-16 E6 results in marked sensitivity to tamoxifen-mediated apoptosis bu
t that resistance to apoptosis rapidly develops within 10 passages in vitro
, Observations in our model system predict a critical role for the early in
stitution of tamoxifen chemoprevention.