The intracellular mechanisms of phytoestrogen protection against cellular proliferation of breast cancers might be via: (1) binding to nuclear ER and inhibiting genomic ER-mediated gene expression, (2) interaction with membrane ER, blocking protein kinases and suppressing transcription factors, (3) inhibiting GFR activation and its downstream signaling networks, (4) activating caspases to initiate cellular apoptosis, (5) reducing the G-protein mediated signaling pathway in the ER-negative mammary cancer cell [red hammers and blue arrows in Fig. 2]. This evidence concerns the gene ESR1 and breast cancer.