Metastasis of Breast Cancer Promoted by Circadian Rhythm Disruption due to Light/Dark Shift and its Prevention by Dietary Quercetin in Mice

Abstract

Epidemiological studies have indicated that a disturbed circadian rhythm resulting from night-shift work is a potential risk factor for breast cancer. However, the mechanism of increased risk of breast cancer by night-shift work remains unclear, and there have been few in vivo studies conducted to definitively associate the two factors. In this study, BJMC3879Luc2 mouse breast cancer cells were transplanted into BALB/c mice. Mice were maintained under lighting conditions that modeled the two-shift system and were investigated for the effect of light/dark cycle disruption on tumor growth and lymph node metastasis. Circadian dysfunction, which was confirmed by measuring circadian locomotor activities using a nano tag device in our light/dark shift model, did not affect tumor growth. However, a significant increase in the number of lymph nodes with distant metastasis was observed. Neutrophil-to-lymphocyte ratio, which is an adverse prognostic factor of breast cancer and also indicator of inflammation, also increased. It has been demonstrated that a chronic inflammatory response is associated with cancer malignancy and poor prognosis in various cancers. These results suggest that night-shift work may also affect distant metastasis and prognosis. In addition, we investigated whether dietary quercetin has anti-metastatic activity against light/dark shift-induced metastasis. A diet containing 0.3 % quercetin significantly inhibited distant lymph node metastasis, particularly metastasis to the iliac and kidney lymph nodes. Our results contribute to our understandings of the effects of the external light environment on breast cancer metastasis and provide a glimpse into potential protective effects of dietary quercetin on light/dark disturbance-induced metastasis.

Forces at play: exploring factors affecting the cancer metastasis

“…In brief, disruption of circadian rhythm aggravates the stemness and tumor-initiating potential of tumor cells, thus diminishing the antitumor immunity ( 268 ). Similarly, disruption of the circadian cycle affects distant lymph node metastasis in a transplantation-arbitrated breast carcinoma without distressing the tumor growth at the primary site ( 269 ).…”

Major roles of the circadian clock in cancer

“…Previous epidemiological investigations have revealed a lack of correlation between circadian clock disorders and the development of specific cancers. However, according to the International Agency for Research on Cancer (IARC) and other recent research, when the human circadian clock is disrupted, the likelihood of developing cancer, including lung cancer, intestinal cancer, and breast cancer, dramatically increases 5,[40][41][42][43][44][45][46] . The above controversy may be due to the use of different research methods, or differences in sample size and representativeness.…”

Circadian rhythm and disease: Relationship, new insights, and future perspectives

“…An epidemiological study associated nightshift work with a higher risk of breast cancer. Exposure of mice to light/dark shift systems resulted in circadian dysfunction and in an increase in lymph nodes with distant metastasis (Numata et al, 2021). Nightshift work impact was studied on breast cancer risk in 1900 Korean women.…”