SLC5A8-Mediated Switching of STAT3 from a Pro-Oncogenic Signal into a Pro-Apoptotic Signal in Breast Cancer

PUBLIC ABSTRACT

According to the most recent National Cancer Institute report, approximately 10 million Americans are currently alive with a history of cancer, and breast cancer is one of the leading causes of death among American women. Breast cancer affects about one in seven women, and current estimates place the average woman's lifetime risk of developing breast cancer at 14.3%. Thus, a clear understanding of the mechanisms involved in the pathogenesis of this dreadful disease and development of more effective therapies than those currently available for the control of the disease are truly needed. The pathogenesis of breast cancer is a genetic war between oncogenes and tumor suppressor genes. In normal cells, there is an absolute balance between these types of genes, but the tumorigenesis would be the ultimate victory of the oncogene.

The mammary gland primarily develops after birth, with ductal branching and elongation, resulting in an epithelial tree that fills the mammary fat pad by end of puberty. During pregnancy, lobuloalveolar units develop and undergo terminal differentiation before parturition, thus allowing milk production. During involution, there is extensive apoptosis of alveolar epithelial cells followed by structural remodeling of the mammary gland, ultimately reaching the pre-pregnant stage. Several molecules are involved in this tightly regulated signaling pathway. STAT3 (Signal transducer and activator of transcription 3) is one of the important molecules involved in mammary gland involution. During mammary gland involution, the physiological apoptosis is induced by a switch from survival to death signaling, and dysregulation of this process is frequently associated with cancer. STAT3 expression is induced and activated in early onset of involution, and mammary gland specific conditional deletion of this gene is associated with involution delay and mastitis, and ultimately induces mammary tumorigenesis. However, STAT3 activation is associated with development of several tumors including breast cancer. How a gene that plays a crucial role in mammary gland regression by activation of apoptotic machinery becomes pro-oncogenic by inactivation of the same apoptotic signaling is not known. Our studies have shown that one of the tumor suppressor genes, SLC5A8, a membrane transporter of butyrate, pyruvate, lactate, and nicotinate, could be the molecular switch for STAT3-associated pro-apoptotic function during mammary gland involution and pro-oncogenic function in mammary tumor formation.

It has long been known that accumulation of breast milk, during involution, induces apoptosis, but the molecular mechanism responsible for this milk stasis-induced apoptotic signaling is not known. We hypothesized that there may be two potential mechanisms that might underlie this milk stasis-initiated apoptosis during mammary gland involution: (i) increased stretching caused by milk accumulation might activate the signaling events that lead to cellular apoptosis and (ii) substances present in the breast milk may itself initiate the apoptotic signaling. To test our hypothesis, we subjected the mammary epithelial cells to mechanical stretching; a process that stimulates cellular stretching that is similar to milk stasis-induced stretching of the mammary epithelium. The results obtained showed that mechanical stretching dramatically increases SLC5A8 expression. The increased expression of the transporter would mediate the entry of butyrate, produced by the breakdown of butyrate-containing triglycerides in the breast milk. Interestingly, the mechanical stretching-induced SLC5A8 is associated with activation of STAT3 expression. Therefore, SLC5A8 and STAT3 are regulated by a common signaling mechanism and play a crucial role in the initiation and regulation of apoptotic signaling in early onset of mammary gland involution. However, we found that more than 90% of human primary breast cancers silence this transporter with concomitant activation of STAT3 expression. The reciprocal relationship between these two genes is not known. We hypothesize that SLC5A8 could be the signaling molecule that converts STAT3 associated pro-survival signal into pro-apoptotic during mammary gland involution. During mammary tumor development, SLC5A8 is inactivated and there is no signal transducer to convert the STAT3-associated pro-survival signaling and thus STAT3 involved in mammary tumor formation. The proposed studies will provide new insight into the basic mechanism of breast cancer development, which should aid in the design and development of novel therapeutic strategies for the prevention and treatment of this disease.