Female sex hormones, the octamer-binding transcription factor 4 (OCT4), and human endogenous retroviruses (HERVs) are all involved in the development of breast cancer. However, whether there are cross talks between these factors to promote breast cancer is still unknown. Using the T47D human breast cancer cell line, we have found that estradiol and progesterone synergistically activate HERV-K through nuclear receptors. The progesterone receptor (isoform B) binds a progesterone-response element (PRE) in a long terminal repeat (LTR5HS) of HERV-K. There is another transcription factor-binding element in the LTR, the octamer motif, which is required for the hormones to activate gene transcription downstream of the LTR. Gel shift assays and co-immunoprecipitation indicate that the progesterone receptor (PR) and the OCT4 transcription factor interact on the protein level. Methylation of the PRE enhances binding of the PR. These findings help to elucidate the previously unknown cross talks among the sex hormones, OCT4, and HERVs in contributing to breast cancer proliferation and tumorigenesis, which may be useful in guiding further development of cancer therapies.