Tamoxifen selects for breast cancer cells with self-renewing capacity and increased growth rate.

RAFFO; PONTIGGIA; BERARDI; TODARO; BAL DE KIER JOFFÉ; SIMIAN

BREAST CANCER RESEARCH AND TREATMENT

SPRINGER

Lugar: Berlin; Año: 2013 vol. 142 p. 537 - 548

0167-6806

Using the M05 mouse mammary tumor model and MCF-7 cells we investigated the effect of tamoxifen treatment on the fraction of breast cancer cells with self-renewing capacity both in vitro and in vivo. We find that pre-treatment with tamoxifen leads to an increase in cells with the capacity of forming mammospheres that express lower levels of ER-α and increased expression of transcription factors associated with pluripotency. Moreover, exposure on plastic to tamoxifen by itself leads to an increase in these transcription factors. M05 tumors grown in mice treated with tamoxifen have a higher percentage of cells with self-renewing capacity and this proportion is conserved when tumors are passaged to non-treated mice. Furthermore, interruption of tamoxifen leads to increased tumor growth compared to tumors grown in mice that were never exposed to the anti-estrogen. Additionally these tumors are characterized by an increase in CD24lCD29h cells compared to the tumors derived from non-treated mice. Treatment in vitro with tamoxifen for 5 days leads to a long lasting increase in the proportion of cells with self-renewing capacity even after one month of growth in the absence of the anti-estrogen. Finally we compared the mammosphere forming capacity of hormone dependent and independent passages of the M05 tumor and found that hormone independence is associated to an increase in cells with self-renewal capacity. Our results support previous findings that suggest that endocrine-treatment selects for cells with self-renewing capacity, and support the notion that extending tamoxifen treatment over 5 years may be recommendable.