Estrogen (E2) has multiple functions in breast
cancers including stimulating
cancer growth and interfering with chemotherapeutic efficacy.
Heteronemin, a marine sesterterpenoid-type natural product, has cytotoxicity on
cancer cells.
Breast cancer cell lines, MCF-7 and MDA-MB-231, were used for investigating mechanisms involved in inhibitory effect of E2 on
heteronemin-induced anti-proliferation in
breast cancer cells with different
estrogen receptor (ER) status. Cytotoxicity was detected by cell proliferation assay and flow cytometry, gene expressions were determined by qPCR, mechanisms were investigated by Western blot and Mitochondrial ROS assay.
Heteronemin exhibited potent cytotoxic effects against both ER-positive and ER-negative
breast cancer cells. E2 stimulated cell growth in ER-positive
breast cancer cells.
Heteronemin induced anti-proliferation via suppressing activation of ERK1/2 and STAT3.
Heteronemin suppressed E2-induced proliferation in both
breast cancer cells although some gene expressions and anti-proliferative effects were inhibited in the presence of E2 in MCF-7 and MDA-MB-231 cells with a higher concentration of
heteronemin. Heteromenin decreased the Bcl-2/Bax ratio to inhibit proliferation in MDA-MB-231 but not in MCF-7 cells. Both
heteronemin and E2 increased mitochondrial
reactive oxygen species but combined treatment reversed
superoxide dismutase (SOD)s accumulation in MCF-7 cells.
Heteronemin caused G0/G1 phase arrest and reduced the percentage of cells in the S phase to suppress
cancer cell growth. In conclusion,
Heteronemin suppressed both ER-positive and ER-negative
breast cancer cell proliferation. Interactions between E2 and
heteronemin in signal transduction, gene expressions, and biological activities provide insights into the complex pathways by which anti-proliferation is induced by
heteronemin in E2-replete environments.