A new study presented at the current annual American Association for Cancer Research (AACR) meeting has reported that retinoic acid, a derivative of vitamin A, is able to reverse the early stages of the tumor development process. The study was designed to investigate the potential of retinoic acid to inhibit or reverse cancer development using a laboratory model of breast cancer progression developed by the authors. Vitamin A, or retinol, is found in animal foods such as liver and whole milk, and in some fortified processed foods. Certain carotenoids such as beta-carotene are also efficiently converted into retinol. Once retinol is converted into its bioactive form, retinoic acid, it plays important roles in cell division, cell death, and cell differentiation. Retinoids such as retinoic acid have been recognized as having potential as anticancer compounds. The actions of retinoids are mediated by retinoic acid receptors, including retinoic acid receptor β (RARβ).
The cancer progression model used by the authors was comprised of four cell lines: (1) MCF-10F cells, which do not have any invasiveness or tumor formation characteristics and therefore are considered to be similar to normal breast cells; (2) transformed trMCF cells which give rise to solid masses when exposed to carcinogens; (3) invasive bsMCF cells; and (4) caMCFs, which have all the characteristics of fully malignant breast cancer cells. In other words, the four cell types model the transition from normal to invasive to fully malignant breast cancer. When injected into the mammary fat pad of immunodeficient mice, the invasive bsMCF cells induced the development of poorly differentiated tumors that were estrogen receptor negative (ER-), progesterone receptor negative (PR-) and ERBB2 negative (in other words, triple negative).
The authors studied the effects of retinoic acid at the different stages of breast cancer progression using cultures of the four cell lines. Cultivating normal breast epithelial cells in collagen causes the cells to polarize and spontaneously differentiate tubular structures. Similarly, MCF-10F cells form tubules resembling the normal mammary gland when cultivated in collagen. The transformed trMCF cells form tubules and spherical masses, which are a marker of cell transformation. One solid trMCF mass was isolated and the cells expanded, resulting in a trMCF clone 11, which only forms solid masses in collagen. The trMCF clone 11 cells were then treated with various concentrations of retinoic acid over a period of 15 days, after which the cells were plated in collagen. A reduction in solid masses and corresponding increase in tubules was observed when trMCF clone 11 cells were treated with retinoic acid. However, retinoic acid did not change the appearance of the invasive bsMCF cells or the malignant caMCF cells even when treated with a compound designed to reactivate the expression of RARβ. The authors conclude that retinoic acid can stop early tumor progression. However, at later time points, the genetic changes related to cancer have progressed too far for retinoic acid to alter the invasive or malignant characteristics of the cells.