Sex cycle modulates cancer growth.

Hypothesis: Among premenopausal women, both post-resection metastatic potential and tumor growth rate are influenced by the menstrual cycle. There is strong support for the former in large retrospective studies of surgical resection timing within the menstrual cycle and the following experiments were conducted to critically evaluate the latter.

Methods: We studied a transplantable breast cancer of C3HeB/FeJ mice (3 studies), and a transplantable methylcholantherene A induced sarcoma of CD2F1 mice (2 studies). We concurrently measured local cancer size and estrous cycle stage up to twice and at least once each day. There is a natural individual variability in the average length of normal estrus (3-1/2 to 7 days) cycle in mice. We assessed the effect of the cycle stage and cycle duration on tumor size.

Results: We found identical estrous cycle stage coordination of cancer size, and identical effects of cycling frequency across all studies in each of these two tumors, both of which express both estrogen receptor alpha and progesterone receptor. Little or no change in cancer size occurs during proestrus (preovulatory phase) and estrus (periovulatory phase); tumor size increases several fold during diestrus (post-ovulatory phase); and the tumor shrinks partially as the next proestrus phase is approached. Across both mouse strains and tumor types, mice whose average cycle length is briefer (faster cyclers), have slower average tumor growth rate than those with longer cycles (slower cyclers) who have faster tumor growth rates.

Conclusion: The virtually identical modulation of tumor size and cancer growth rate, in each of two very different transplantable cancers (one, classically sex-hormone-dependent, and the other, never previously recognized as hormone dependent) growing in two unrelated inbred mouse strains, indicates that the fertility cycle related host factors affect cancer size and growth rate. These experimental findings suggest that cancer cell proliferation of both breast and non-breast cancers in premenopausal women may be meaningfully coordinated by the menstrual cycle. If this proves to be the case, then any therapeutic strategy targeting proliferating cancer cells should be most effective against cancer of cycling women when given during the follicular phase of their menstrual cycles.