Figure 4. Proposed model for the generation of pregnancy-associated TNBCs.

We propose that an oncogene(s) is overexpressed (lighting bolt) by pregnant and lactating cells to perform a specific function such as excess proliferation and survival. Since the cells overexpressing that oncogene must die before the mammary gland returns to pre-pregnancy stage, two outcomes depending on the duration of breastfeeding could be envision. The first is an oncogene-elimination outcome, in which during the longer duration of breastfeeding ( > 12 months) all oncogene-overexpressing cells undergo a full differentiation program. These terminally differentiated mammary cells are also immune-presenting and therefore will be detected and eliminated by the immune cells infiltrating the mammary gland during normal involution and replaced by newly low oncogene-expressing cells. The second is oncogene-escape outcome, in which during shorter (or no) duration of breastfeeding ( < 12 months), many of the oncogene-overexpressing cells are still in the stem/progenitor stage. During forced involution and the influx of immune cells that ensues, oncogene-expressing terminally differentiated cells will be recognized and eliminated as described above, whereas the oncogene-expressing stem/progenitor cells will escape immune system recognition and elimination and instead thrive, flourish and become pregnancy-associated TNBC precursors in this inflammatory microenvironment, that develop 2-5 years following this pregnancy.