Data from: An experimental analysis of the molecular effects of trastuzumab (herceptin) and fulvestrant (falsodex), as single agents or in combination, on human HR+/HER2+ breast cancer cell lines and mouse tumor xenografts

Purpose: To investigate the effects of trastuzumab (herceptin) and
fulvestrant (falsodex) either in combination or alone, on downstream cell
signaling pathways in lab-cultured human HR+/HER2+ breast cancer cell
lines ZR-75-1 and BT-474, as well as on protein expression levels in mouse
xenograft tissue. Methods: Cells were cultivated in the presence of
trastuzumab or fulvestrant or both. Molecular events that resulted in an
inhibition of cell proliferation and cell cycle progression or in an
increased rate of apoptosis were studied. The distribution and abundance
of the proteins p-Akt and p-Erk expressed in these cells in response to
single agents or combinatorial treatment were also investigated. In
addition, the effects of trastuzumab and fulvestrant, either as single
agents or in combination on tumor growth as well as on expression of the
protein p-MED1 expressed in in vivo mouse xenograft models was also
examined. Results: Cell proliferation was increasingly inhibited by
trastuzumab or fulvestrant or both, with a CI<1 and DRI>1 in
both human cell lines. The rate of apoptosis increased only in the BT-474
cell line and not in the ZR-75-1 cell line upon treatment with fulvestrant
and not trastuzumab as a single agent (P<0.05). Interestingly,
fulvestrant, in combination with trastuzumab, did not significantly alter
the rate of apoptosis (in comparison with fulvestrant alone), in the
BT-474 cell line (P>0.05). Cell accumulation in the G1 phase of
cell cycle was investigated in all treatment groups (P<0.05), and
the combination of trastuzumab and fulvestrant reversed the effects of
fulvestrant alone on p-Akt and p-Erk protein expression levels. Using
ZR-75-1 or BT-474 to generate in vivo tumor xenografts in BALB/c athymic
mouse models, we showed that a combination of both drugs resulted in a
stronger inhibition of tumor growth (P<0.05) and a greater decrease
in the levels of activated MED1 (p-MED1) expressed in tumor issues
compared with the use of either drug as a single agent. Conclusions: We
demonstrate that the administration of trastuzumab and fulvestrant in
combination results in positive synergistic effects on both, ZR-75-1 and
BT-474 cell lines. This combinatorial approach is likely to reduce
physiological side effects of both drugs, thus providing a theoretical
basis for the use of such combination treatment in order to resolve
HR+/HER2+ triple positive breast cancer that has previously been shown to
be resistant to endocrine treatment alone.