A few clinical investigations suggest that while primary breast cancer surgical removal favorably modifies the natural history for some patients, it may also hasten the metastatic development for others. The concepts underlying this disease paradigm, i.e. tumor homeostasis, tumor dormancy and surgery-driven enhancement of metastasis development, have a long history that is reviewed. The review reveals the context in which these concepts were conceived and structured to explain experimental data and shows that they are not so new and far fetched. The idea that surgical cancer resection has both beneficial and adverse effects upon cancer spread and growth that result from the modulation of tumor dormancy by the resection should be considered a potentially fruitful working hypothesis.

We studied the relative RNA expression of clock genes throughout one 24-hour period in biopsies obtained from the oral mucosa and skin from eight healthy diurnally active male study participants. We found that the human clock genes hClock, hTim, hPer1, hCry1, and hBmal1 are expressed in oral mucosa and skin, with a circadian profile consistent with that found in the suprachiasmatic nuclei and the peripheral tissues of rodents. hPer1, hCry1, and hBmal1 have a rhythmic expression, peaking early in the morning, in late afternoon, and at night, respectively, whereas hClock and hTim are not rhythmic. This is the first human study to show a circadian profile of expression for all five clock genes as documented in rodents, suggesting their functional importance in man. In concurrent oral mucosa biopsies, thymidylate synthase enzyme activity, a marker for DNA synthesis, had a circadian variation with peak activity in early afternoon, coinciding with the timing of S phase in our previous study on cell-cycle timing in human oral mucosa. The major peak in hPer1 expression occurs at the same time of day as the peak in G(1) phase in oral mucosa, suggesting a possible link between the circadian clock and the mammalian cell cycle.

Primary tumor removal, usually considered intrinsically beneficial, can perturb metastatic homeostasis, and for some patients results in the acceleration of metastatic cancer. The continuous-growth model is required to yield to an interrupted-growth model, the implications of which are episodes of tumor dormancy. This Review analyzes the recent evolution of two paradigms related to the development of breast cancer metastases. The evolution of the paradigms described herein is supported by a growing body of findings from experimental models, and is required to explain breast cancer recurrence dynamics for patients undergoing surgery with or without adjuvant chemotherapy.