| dc.description.abstract |
The presence of estrogen receptor α (ER-α) in breast tumors predicts the patient
response to hormone therapy. The most common treatments are the antiestrogens 4-
hydroxy tamoxifen (Tam) and fulvestrant (ICI 182,780). While Tam exhibits partial
agonistic activities, ICI is a total antagonist. Most patients eventually develop resistance
to antiestrogens. Identifying cellular pathways which enable hormone sensitive and
hormone resistant breast cancer cells to continue growing will help determine the
direction of future therapy. To study the acquired hormone resistance of MCF7 breast
cancer cells during endocrine treatment, specifically the role of antiestrogens, epidermal
growth factor receptor II (ErbB2), and the phosphoinositide 3-kinase/ serine/threonine
protein kinase 1(PI 3-K/Akt1) pathway, I used three variants of MCF7 cells. Parental
MCF7 cells are estrogen-dependent and responsive to antiestrogens, Tam and ICI
182,780. LCC1 cells grow independently of estrogen, but are sensitive to Tam and ICI
182,780. LCC2 and LCC9 cells were generated from LCC1 cells that underwent long-
term treatment with antiestrogens, Tam and ICI 182,780, respectively. LCC2 and LCC9
grow estrogen-independently and are antiestrogen resistant. RNA was extracted from
MCF7/LCC1, 2, and 9 cells under estradiol (E2) treatment in the presence or absence of
antiestrogens, ErbB2 and/or PI 3-K inhibitors to determine the effect of these treatments
on ER-α activity by real time RT-polymerase chain reaction (PCR). The mRNA
induction was measured for the progesterone receptor (PGR), an estrogen-dependent
gene, and compared to the internal control, glyceraldehyde-3-phosphate dehydrogenase
(GAPDH) mRNA induction. Results are compared in MCF7 cells versus LCC cells. In
MCF7/LCC cells, PGR mRNA is induced upon E2 treatment. This effect is inhibited by
both Tam and ICI 182,780 only in MCF7 and LCC1 cells. Tam and ICI 182,780 also
increase PGR mRNA in LCC2 and LCC9 cells, respectively. The E2 effect and
antiestrogen resistance was stably inhibited by both inhibitors of ErbB2, AG825, and PI
3-K, LY 294,002. The data support that activation of ErbB2 and PI 3-K/Akt1 signaling
pathway can overcome the antiestrogenic effects of Tam and ICI 182,780. Results
demonstrate the ability of the selective ErbB2 inhibitor, AG825, and the PI 3-K inhibitor,
LY 294,002 to inhibit cell growth after breast cancer cells have developed resistance to
antiestrogens, Tam and ICI 182,780. Further studies of the effects of the AG825 and LY
294,002 are needed to determine their reliability and the practical clinical use of these
findings for those patients who have developed resistance to antiestrogens. |
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