The Role of ALDH1A3 in Normal and Transformed Mammary Gland Development

Abstract

Aldehyde dehydrogenases (ALDHs) have been used as stem cell markers in a variety of tissues, including the breast. However, it is currently unknown whether ALDH family members participate in normal mammary development or breast cancer. In this study, we set out to elucidate a role for one such protein, ALDH1A3, in mammary luminal cell differentiation and tumorigenesis. We have identified three ALDH1A3 splice variants in breast cell lines, raising the question of whether alternative splicing contributes to cancer development by altering ALDH1A3 activity. We also observed impaired cell motility and defective differentiation in normal breast cell lines cultured in the presence of diethylaminobenzaldehyde (DEAB), a general inhibitor of ALDH activity, suggesting that certain ALDH family members are important for these processes. Based on preliminary in vitro experiments monitoring morphology of breast cell line acini formation and differentiation, doxycyclin-inducible lentiviral TRIPZ-shALDH1A3 pools did not show any obvious defects in differentiation. In addition to this finding, ALDH1A3 mRNA expression levels in primary breast tumour samples (n=39) did not significantly correlate with age, histological grade or hormone receptor status (p-value>0.05). Overall, the results of this study suggest that while ALDH1A3 itself may not be directly involved in breast morphogenesis or cancer formation, other ALDH family members function to facilitate differentiation and cell motility, processes which are important both for normal mammary gland development as well as cancer progression and metastasis.